|
1
|
Zhang L, Li P, Li Y, Qu W, Shi Y, Zhang T, Chen Y. The role of immunoglobins in atherosclerosis development; friends or foe? Mol Cell Biochem 2025; 480:2737-2747. [PMID: 39592554 DOI: 10.1007/s11010-024-05158-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024]
Abstract
Coronary artery disease, atherosclerosis, and its life-threatening sequels impose the hugest burden on the healthcare systems throughout the world. The intricate process of atherosclerosis is considered as an inflammatory-based disorder, and therefore, the components of the immune system are involved in different stages from formation of coronary plaques to its development. One of the major effectors in this way are the antibody producing entities, the B cells. These cells, which play a significant and unique role in responding to different stress, injuries, and infections, contribute differently to the development of atherosclerosis, either inhibitory or promoting, depending on the type of subsets. B cells implicate in both systemic and local immune responses of an atherosclerotic artery by cell-cell contact, cytokine production, and antigen presentation. In particular, natural antibodies bind to oxidized lipoproteins and cellular debris, which are abundant during plaque growth. Logically, any defects in B cells and consequent impairment in antibody production may greatly affect the shaping of the plaque and its clinical outcome. In this comprehensive review, we scrutinize the role of B cells and different classes of antibodies in atherosclerosis progression besides current novel B-cell-based therapeutic approaches that aim to resolve this affliction of mankind.
Collapse
Affiliation(s)
- Linlin Zhang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Peize Li
- Department of Orthopedics, Changchun Chinese Medicine Hospital, Changchun, 130022, China
| | - Yuhui Li
- Department of Cardiology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China
| | - Wantong Qu
- Department of Cardiology, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China
| | - Yanyu Shi
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Tianyang Zhang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, 130117, China
| | - Ying Chen
- Department of Cardiology, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, 130021, China.
| |
Collapse
|
|
2
|
Liu M, Xu Y, Song Y, Fan D, Li J, Zhang Z, Wang L, He J, Chen C, Ma C. Hierarchical Regulatory Networks Reveal Conserved Drivers of Plant Drought Response at the Cell-Type Level. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2415106. [PMID: 40091436 PMCID: PMC12079547 DOI: 10.1002/advs.202415106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 01/29/2025] [Indexed: 03/19/2025]
Abstract
Drought is a critical environmental challenge affecting plant growth and productivity. Understanding the regulatory networks governing drought response at the cellular level remains an open question. Here, a comprehensive multi-omics integration framework that combines transcriptomic, proteomic, epigenetic, and network-based analyses to delineate cell-type-specific regulatory networks involved in plant drought response is presented. By analyzing nearly 30 000 multi-omics data samples across species, unique insights are revealed into conserved drought responses and cell-type-specific regulatory dynamics, leveraging novel integrative analytical workflows. Notably, CIPK23 emerges as a conserved protein kinase mediating drought tolerance through interactions with CBL4, as validated by yeast two-hybrid and BiFC assays. Experimental validation in Arabidopsis thaliana and Vitis vinifera confirms the functional conservation of CIPK23, which enhances drought resistance in overexpression lines. In addition, the authors' causal network analysis pinpoints critical regulatory drivers such as NLP7 and CIPK23, providing insights into the molecular mechanisms of drought adaptation. These findings advance understanding of plant drought tolerance and offer potential targets for improving crop resilience across diverse species.
Collapse
Affiliation(s)
- Moyang Liu
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Yuanyuan Xu
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Yue Song
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Dongying Fan
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Junpeng Li
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Zhen Zhang
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Lujia Wang
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Juan He
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Cheng Chen
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| | - Chao Ma
- School of Agriculture and BiologyShanghai Jiao Tong UniversityShanghai200240China
| |
Collapse
|
|
3
|
Bartoloni E, Cacciapaglia F, Erre GL, Gremese E, Manfredi A, Piga M, Sakellariou G, Spinelli FR, Viapiana O, Atzeni F. Immunomodulation for accelerated atherosclerosis in rheumatoid arthritis and systemic lupus erythematosus. Autoimmun Rev 2025; 24:103760. [PMID: 39894242 DOI: 10.1016/j.autrev.2025.103760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/04/2025]
Abstract
In the last decades, consisting evidence supported a close relationship between both innate and adaptive immune systems and the accelerated cardiovascular (CV) disease characterizing autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Indeed, several cell lines involved in the pathogenesis of these autoimmune diseases, such as macrophages and dendritic cells, as well as different T and B lymphocyte subsets, and inflammatory cytokines, have been demonstrated to be directly involved in the mechanisms underlying early atherosclerotic arterial wall damage. Traditional CV risk factors play a concomitant role but do not sufficiently account for the increased prevalence of CV disease in these patients. Indeed, the pathophysiological link between RA and SLE and atherosclerosis is based on complex inflammatory pathways that interconnect these conditions and may explain the significant morbidity and mortality rates demonstrated in these patients, with consequent significant negative effects on quality of life and long-term survival. Consequently, it is intriguing to hypothesize that immunosuppressive drugs commonly used in the treatment of these pathologies may also exert an immunomodulatory and anti-inflammatory effect in mitigating the atherosclerotic damage that has been demonstrated to occur early in the initial stages of the disease. Recognizing risk factors, predicting occurrences and early intervention to prevent CV disease development have emerged as critical objectives in RA and SLE treatment. In this review, we aimed to provide an updated overview of the atherogenic effects exerted by the immune and inflammatory pathways involved in the pathogenesis of RA and SLE. Moreover, we examined the available evidence which may support the potential effects of immunosuppressive therapies in reducing CV damage and, consequently, CV disease risk in these patients.
Collapse
Affiliation(s)
- Elena Bartoloni
- Rheumatology Unit, Department of Medicine and Surgery, University of Perugia, Italy
| | - Fabio Cacciapaglia
- Rheumatology Unit, Department of Precision and Regenerative Medicine and Ionian Area (DePReMeI), University of Bari, Bari, Italy; Department of Medicine and Surgery, LUM University "Giuseppe De Gennaro" Casamassima & Rheumatology Service "Miulli" General Hospital Acquaviva delle Fonti, Bari, Italy
| | - Gian Luca Erre
- Dipartimento di Scienze Mediche, Chirurgiche e Sperimentali, Università degli Studi di Sassari, Italy
| | - Elisa Gremese
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Andreina Manfredi
- University of Modena and Reggio Emilia,AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy
| | - Matteo Piga
- Rheumatology Unit, AOU Cagliari, Department of Medical Sciences and Public Health, University of Cagliari, Italy
| | - Garifallia Sakellariou
- Department of Internal Medicine and Therapeutics, University of Pavia, Istituti Clinici Scientifici Maugeri, Pavia, Italy
| | - Francesca Romana Spinelli
- Reumatology Unit, Department of Internal, Anesthesiological, and Cardiovascular Clinical Sciences, Sapienza University of Rome, Rome, Italy
| | - Ombretta Viapiana
- Rheumatology Unit, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Italy
| | - Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Italy.
| |
Collapse
|
|
4
|
Juhasz V, Charlier FT, Zhao TX, Tsiantoulas D. Targeting the adaptive immune continuum in atherosclerosis and post-MI injury. Atherosclerosis 2024; 399:118616. [PMID: 39546915 DOI: 10.1016/j.atherosclerosis.2024.118616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 09/04/2024] [Accepted: 09/24/2024] [Indexed: 11/17/2024]
Abstract
Atherosclerotic disease is a cholesterol-rich lipoprotein particle-driven disease resulting in the formation of atherosclerotic plaques in large and medium size arteries. Rupture or erosion of atherosclerotic plaques can trigger the formation of a thrombus causing the obstruction of the blood flow in the coronary artery and thereby leading to myocardial infarction (MI). Inflammation is a crucial pillar of the mechanisms leading to atherosclerosis and governing the cardiac repair post-MI. Dissecting the complex and sophisticated networks of the immune responses underlying the formation of atherosclerotic plaques and affecting the healing of the heart after MI will allow the designing of highly precise immunomodulatory therapies for these settings. Notably, MI also accelerates atherosclerosis via modulating the response of the immune system. Therefore, for the identification of effective and safe therapeutic targets, it is critical to consider the inflammatory continuum that interconnects the two pathologies and identify immunomodulatory strategies that confer a protective effect in both settings or at least, affect each pathology independently. Adaptive immunity, which consists of B and T lymphocytes, is a major regulator of atherosclerosis and post-MI cardiac repair. Here, we review and discuss the effect of potential adaptive immunity-targeting therapies, such as cell-depleting therapies, in atherosclerosis and post-MI cardiac injury.
Collapse
Affiliation(s)
- Viktoria Juhasz
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Fiona T Charlier
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Tian X Zhao
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Department of Cardiology, Royal Papworth Hospital NHS Trust, Cambridge, United Kingdom
| | | |
Collapse
|
|
5
|
Takaoka M, Zhao X, Lim HY, Magnussen CG, Ang O, Suffee N, Schrank PR, Ong WS, Tsiantoulas D, Sommer F, Mohanta SK, Harrison J, Meng Y, Laurans L, Wu F, Lu Y, Masters L, Newland SA, Denti L, Hong M, Chajadine M, Juonala M, Koskinen JS, Kähönen M, Pahkala K, Rovio SP, Mykkänen J, Thomson R, Kaisho T, Habenicht AJR, Clement M, Tedgui A, Ait-Oufella H, Zhao TX, Nus M, Ruhrberg C, Taleb S, Williams JW, Raitakari OT, Angeli V, Mallat Z. Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis. Nature 2024; 634:457-465. [PMID: 39231480 PMCID: PMC11464399 DOI: 10.1038/s41586-024-07993-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Accepted: 08/27/2024] [Indexed: 09/06/2024]
Abstract
Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk1. Furthermore, LDL-C fluctuations are associated with ASCVD outcomes2-4. However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1+ resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD.
Collapse
MESH Headings
- Adolescent
- Adult
- Animals
- Child
- Child, Preschool
- Female
- Humans
- Male
- Mice
- Middle Aged
- Young Adult
- Atherosclerosis/epidemiology
- Atherosclerosis/etiology
- Atherosclerosis/genetics
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Cholesterol, LDL/blood
- Cholesterol, LDL/metabolism
- Diet, Western/adverse effects
- Diet, Western/statistics & numerical data
- Finland/epidemiology
- Genome-Wide Association Study
- Hyperlipidemias/complications
- Hyperlipidemias/epidemiology
- Hyperlipidemias/genetics
- Hyperlipidemias/metabolism
- Hyperlipidemias/pathology
- Incidence
- Macrophages/metabolism
- Macrophages/pathology
- Mice, Inbred C57BL
- Phenotype
- Plaque, Atherosclerotic/epidemiology
- Plaque, Atherosclerotic/etiology
- Plaque, Atherosclerotic/genetics
- Plaque, Atherosclerotic/metabolism
- Plaque, Atherosclerotic/pathology
- Time Factors
Collapse
Affiliation(s)
- Minoru Takaoka
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Xiaohui Zhao
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Hwee Ying Lim
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Costan G Magnussen
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Owen Ang
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Nadine Suffee
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Patricia R Schrank
- Department of Integrative Biology & Physiology, Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Wei Siong Ong
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Dimitrios Tsiantoulas
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Felix Sommer
- Institute of Clinical Molecular Biology, University of Kiel and University Hospital Schleswig Holstein (UKSH), Kiel, Germany
| | - Sarajo K Mohanta
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - James Harrison
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Yaxing Meng
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Ludivine Laurans
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Feitong Wu
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Yuning Lu
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Leanne Masters
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Stephen A Newland
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Laura Denti
- Institute of Ophthalmology, University College London, London, UK
| | - Mingyang Hong
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Mouna Chajadine
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Markus Juonala
- Department of Medicine, University of Turku, Turku, Finland
- Division of Medicine, Turku University Hospital, Turku, Finland
| | - Juhani S Koskinen
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Division of Medicine, Turku University Hospital, Turku, Finland
- Department of Medicine, Satakunta Central Hospital, Pori, Finland
| | - Mika Kähönen
- Department of Clinical Physiology, University of Tampere, Tampere, Finland
- Faculty of Medicine and Health Technology, University of Tampere, Tampere, Finland
- Finnish Cardiovascular Research Center Tampere, University of Tampere, Tampere, Finland
| | - Katja Pahkala
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Suvi P Rovio
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Juha Mykkänen
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
| | - Russell Thomson
- Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Analytical Edge, Hobart, Tasmania, Australia
| | - Tsuneyasu Kaisho
- Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan
| | - Andreas J R Habenicht
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Marc Clement
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Alain Tedgui
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Hafid Ait-Oufella
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Tian X Zhao
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | - Meritxell Nus
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK
| | | | - Soraya Taleb
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France
| | - Jesse W Williams
- Department of Integrative Biology & Physiology, Center for Immunology, University of Minnesota, Minneapolis, MN, USA
| | - Olli T Raitakari
- Research Centre of Applied and Preventive Cardiovascular Medicine; University of Turku, Turku, Finland
- Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
- Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
| | - Véronique Angeli
- Immunology Translational Research Programme, Yong Loo Lin School of Medicine, Department of Microbiology and Immunology, National University of Singapore, Singapore, Singapore
- Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore
| | - Ziad Mallat
- Department of Medicine, Section of CardioRespiratory Medicine, University of Cambridge, Heart and Lung Research Institute, Cambridge, UK.
- Université Paris Cité, Institut National de la Santé et de la Recherche Médicale, U970, PARCC, Paris, France.
| |
Collapse
|
|
6
|
Chen Z, Wang Z, Cui Y, Xie H, Yi L, Zhu Z, Ni J, Du R, Wang X, Zhu J, Ding F, Quan W, Zhang R, Wang Y, Yan X. Serum BAFF level is associated with the presence and severity of coronary artery disease and acute myocardial infarction. BMC Cardiovasc Disord 2024; 24:471. [PMID: 39227771 PMCID: PMC11370111 DOI: 10.1186/s12872-024-04146-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 08/27/2024] [Indexed: 09/05/2024] Open
Abstract
OBJECTIVE The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear. METHODS Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI. RESULTS Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P < 0.0001) and the GRACE score (r = 0.5684, P < 0.0001). Logistic regression analysis demonstrated that increased BAFF levels were an independent risk factor for CAD (adjusted OR 1.305, 95% CI 1.078-1.580) and AMI (adjusted OR 2.874, 95% CI 1.708-4.838) after adjusting for confounding variables. Additionally, elevated BAFF levels were significantly associated with a high GRACE score (GRACE score 155 to 319, adjusted OR 4.297, 95% CI 1.841-10.030). BAFF exhibited a sensitivity of 75.0% and specificity of 71.4% in differentiating CAD patients with a high SYNTAX score, and a sensitivity of 75.5% and specificity of 72.8% in identifying AMI patients with a high GRACE score. CONCLUSION Circulating BAFF levels serve as a valuable diagnostic marker for CAD and AMI. Elevated BAFF levels are associated with the presence and severity of these conditions, suggesting its potential as a clinically relevant biomarker in cardiovascular disease.
Collapse
Affiliation(s)
- Zhiyong Chen
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Ziyang Wang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yuke Cui
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Hongyang Xie
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Lei Yi
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Zhengbin Zhu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Jingwei Ni
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Run Du
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Xiaoqun Wang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Jinzhou Zhu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Fenghua Ding
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Weiwei Quan
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
| | - Ruiyan Zhang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China.
| | - Yueying Wang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China.
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| | - Xiaoxiang Yan
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China.
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
| |
Collapse
|
|
7
|
Wu Y, Chen S, Huang G, Zhang L, Zhong L, Feng Y, Wen P, Liu J. Transcriptome analysis reveals EBF1 ablation-induced injuries in cardiac system. Theranostics 2024; 14:4894-4915. [PMID: 39239522 PMCID: PMC11373621 DOI: 10.7150/thno.92060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 07/29/2024] [Indexed: 09/07/2024] Open
Abstract
Rationale: Regulatory processes of transcription factors (TFs) shape heart development and influence the adult heart's response to stress, contributing to cardiac disorders. Despite their significance, the precise mechanisms underpinning TF-mediated regulation remain elusive. Here, we identify that EBF1, as a TF, is highly expressed in human heart tissues. EBF1 is reported to be associated with human cardiovascular disease, but its roles are unclear in heart. In this study, we investigated EBF1 function in cardiac system. Methods: RNA-seq was utilized to profile EBF1 expression patterns. CRISPR/Cas9 was utilized to knock out EBF1 to investigate its effects. Human pluripotent stem cells (hPSCs) differentiated into cardiac lineages were used to mimic cardiac development. Cardiac function was evaluated on mouse model with Ebf1 knockout by using techniques such as echocardiography. RNA-seq was conducted to analyze transcriptional perturbations. ChIP-seq was employed to elucidate EBF1-bound genes and the underlying regulatory mechanisms. Results: EBF1 was expressed in some human and mouse cardiomyocyte. Knockout of EBF1 inhibited cardiac development. ChIP-seq indicated EBF1's binding on promoters of cardiogenic TFs pivotal to cardiac development, facilitating their transcriptional expression and promoting cardiac development. In mouse, Ebf1 depletion triggered transcriptional perturbations of genes, resulting in cardiac remodeling. Mechanistically, we found that EBF1 directly bound to upstream chromatin regions of cardiac hypertrophy-inducing genes, contributing to cardiac hypertrophy. Conclusions: We uncover the mechanisms underlying EBF1-mediated regulatory processes, shedding light on cardiac development, and the pathogenesis of cardiac remodeling. These findings emphasize EBF1's critical role in orchestrating diverse aspects of cardiac processes and provide a promising therapeutic intervention for cardiomyopathy.
Collapse
Affiliation(s)
- Yueheng Wu
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, China, 510080
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China, 510080
| | - Shaoxian Chen
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, China, 510080
- Guangdong Provincial Key Laboratory of South China Structural Heart Disease, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China, 510080
| | - Guiping Huang
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
- Guangdong Provincial Key Laboratory of Clinical Pharmacology, Medical Research Center, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, China, 510080
| | - Lu Zhang
- Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong-Hong Kong Joint Laboratory for Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China, 510530
| | - Liying Zhong
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
| | - Yi Feng
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
| | - Pengju Wen
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
| | - Juli Liu
- Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China, 510080
- Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangzhou, Guangdong, China, 510080
| |
Collapse
|
|
8
|
Liang D, Huang S, Ding R. Effects of belimumab on the lipid profile in systemic lupus erythematosus patients: an observational study. Clin Rheumatol 2024; 43:2513-2520. [PMID: 38877375 DOI: 10.1007/s10067-024-07029-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 05/19/2024] [Accepted: 06/09/2024] [Indexed: 06/16/2024]
Abstract
This study is asked to investigate the effects of belimumab on the lipid profile in systemic lupus erythematosus (SLE) patients. Forty-one SLE patients who received at least 6 months of belimumab treatment were retrospectively analyzed. The control group consisted of 56 age- and sex-matched lupus patients not treated with belimumab. The changes in lipid profile after a 6-month treatment were compared between the two groups. Generalized estimating equation (GEE) analyses were performed to examine lipid levels longitudinally during the period and the effect of clinical response variables and medication on the lipid profile in the belimumab group. In the belimumab group, high-density lipoprotein (HDL) cholesterol levels increased significantly after the 6-month treatment (P = 0.02). After 1 month, HDL, apolipoprotein A-I (apoA-I) significantly increased by 13.8 and 11.4%, compared with baseline, respectively. After 3 months, HDL and apoA-I increased by 9.0 and 7.1%, respectively. After 6 months, HDL increased by 7.6% compared with baseline. Total cholesterol, triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B did not change significantly over the course of treatment. GEE analyses indicated a significant association between HDL and disease activity indexes, such as IgG, anti-dsDNA, and complement C3. Subgroup analysis revealed significant changes in HDL only in patients who had achieved a ≥ 4-point reduction in SLEDAI-2 K after 6 months of belimumab treatment. Belimumab treatment may result in a long-term increase in HDL level in SLE patients by improving control of lupus activity. This might have beneficial effects on controlling cardiovascular risk in lupus patients. Key Points • Treatment with belimumab resulted in a significant and sustained increase in the HDL levels in SLE patients. • Significant changes in HDL were observed in lupus patients treated with belimumab who had a better clinical response.
Collapse
Affiliation(s)
- Di Liang
- Department of Rheumatology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Shimei Huang
- Department of Rheumatology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Rui Ding
- Department of Rheumatology, Zhongshan Hospital Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
| |
Collapse
|
|
9
|
Obare LM, Bonami RH, Doran A, Wanjalla CN. B cells and atherosclerosis: A HIV perspective. J Cell Physiol 2024; 239:e31270. [PMID: 38651687 PMCID: PMC11209796 DOI: 10.1002/jcp.31270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 03/09/2024] [Accepted: 03/27/2024] [Indexed: 04/25/2024]
Abstract
Atherosclerosis remains a leading cause of cardiovascular disease (CVD) globally, with the complex interplay of inflammation and lipid metabolism at its core. Recent evidence suggests a role of B cells in the pathogenesis of atherosclerosis; however, this relationship remains poorly understood, particularly in the context of HIV. We review the multifaceted functions of B cells in atherosclerosis, with a specific focus on HIV. Unique to atherosclerosis is the pivotal role of natural antibodies, particularly those targeting oxidized epitopes abundant in modified lipoproteins and cellular debris. B cells can exert control over cellular immune responses within atherosclerotic arteries through antigen presentation, chemokine production, cytokine production, and cell-cell interactions, actively participating in local and systemic immune responses. We explore how HIV, characterized by chronic immune activation and dysregulation, influences B cells in the context of atherosclerosis, potentially exacerbating CVD risk in persons with HIV. By examining the proatherogenic and antiatherogenic properties of B cells, we aim to deepen our understanding of how B cells influence atherosclerotic plaque development, especially within the framework of HIV. This research provides a foundation for novel B cell-targeted interventions, with the potential to mitigate inflammation-driven cardiovascular events, offering new perspectives on CVD risk management in PLWH.
Collapse
Affiliation(s)
- Laventa M. Obare
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Rachel H. Bonami
- Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Amanda Doran
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Celestine N. Wanjalla
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
| |
Collapse
|
|
10
|
Sanges S, Tian W, Dubucquoi S, Chang JL, Collet A, Launay D, Nicolls MR. B-cells in pulmonary arterial hypertension: friend, foe or bystander? Eur Respir J 2024; 63:2301949. [PMID: 38485150 PMCID: PMC11043614 DOI: 10.1183/13993003.01949-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 03/01/2024] [Indexed: 04/22/2024]
Abstract
There is an unmet need for new therapeutic strategies that target alternative pathways to improve the prognosis of patients with pulmonary arterial hypertension (PAH). As immunity has been involved in the development and progression of vascular lesions in PAH, we review the potential contribution of B-cells in its pathogenesis and evaluate the relevance of B-cell-targeted therapies. Circulating B-cell homeostasis is altered in PAH patients, with total B-cell lymphopenia, abnormal subset distribution (expansion of naïve and antibody-secreting cells, reduction of memory B-cells) and chronic activation. B-cells are recruited to the lungs through local chemokine secretion, and activated by several mechanisms: 1) interaction with lung vascular autoantigens through cognate B-cell receptors; 2) costimulatory signals provided by T follicular helper cells (interleukin (IL)-21), type 2 T helper cells and mast cells (IL-4, IL-6 and IL-13); and 3) increased survival signals provided by B-cell activating factor pathways. This activity results in the formation of germinal centres within perivascular tertiary lymphoid organs and in the local production of pathogenic autoantibodies that target the pulmonary vasculature and vascular stabilisation factors (including angiotensin-II/endothelin-1 receptors and bone morphogenetic protein receptors). B-cells also mediate their effects through enhanced production of pro-inflammatory cytokines, reduced anti-inflammatory properties by regulatory B-cells, immunoglobulin (Ig)G-induced complement activation, and IgE-induced mast cell activation. Precision-medicine approaches targeting B-cell immunity are a promising direction for select PAH conditions, as suggested by the efficacy of anti-CD20 therapy in experimental models and a trial of rituximab in systemic sclerosis-associated PAH.
Collapse
Affiliation(s)
- Sébastien Sanges
- Univ. Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
- INSERM, F-59000 Lille, France
- CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), F-59000 Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), F-59000 Lille, France
- Veteran Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, School of Medicine, Stanford, CA, USA
- Both authors contributed equally and share co-first authorship
| | - Wen Tian
- Veteran Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, School of Medicine, Stanford, CA, USA
- Both authors contributed equally and share co-first authorship
| | - Sylvain Dubucquoi
- Univ. Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
- INSERM, F-59000 Lille, France
- CHU Lille, Institut d'Immunologie, Pôle de Biologie Pathologie Génétique, F-59000 Lille, France
| | - Jason L Chang
- Veteran Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, School of Medicine, Stanford, CA, USA
| | - Aurore Collet
- Univ. Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
- INSERM, F-59000 Lille, France
- CHU Lille, Institut d'Immunologie, Pôle de Biologie Pathologie Génétique, F-59000 Lille, France
| | - David Launay
- Univ. Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, F-59000 Lille, France
- INSERM, F-59000 Lille, France
- CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France
- Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), F-59000 Lille, France
- Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases Network (ReCONNET), F-59000 Lille, France
- Veteran Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, School of Medicine, Stanford, CA, USA
- Both authors contributed equally and share co-last authorship
| | - Mark R Nicolls
- Veteran Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford University, School of Medicine, Stanford, CA, USA
- Both authors contributed equally and share co-last authorship
| |
Collapse
|
|
11
|
Zhang Y, Qi X, Wang S, Zhang W, Yang R, Wang X, Chen W, Ji F, Dong J, Yu X. Serum immunoglobulin M is associated with the severity of coronary artery disease in adults. PeerJ 2024; 12:e17012. [PMID: 38464758 PMCID: PMC10921929 DOI: 10.7717/peerj.17012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 02/05/2024] [Indexed: 03/12/2024] Open
Abstract
Purpose The purpose of this study was to investigate the relationship between serum immunoglobulin M (IgM) and the severity of coronary artery disease in Chinese patients who underwent coronary angiography. Methods A total of 2,045 patients who underwent coronary angiography (CAG) from March 2017 to March 2020 at Beijing Hospital were included in this study. Serum IgM concentration and biochemical indicators were measured before coronary angiography (CAG). The triquartile IgM levels at baseline in the population were analysed. Spearman rank correlation was used to analyse the association between IgM and traditional risk factors for coronary artery disease (CAD). CAD patients were divided into subgroups by affected area, number of affected vessels, and Gensini score to analyse the relationship between IgM and CAD severity. Multivariable logistic regression analysis was used to evaluate the association between IgM and CAD severity. Results Serum IgM levels were significantly lower in the CAD group (63.5 mg/dL) than in the non-coronary artery disease (NCAD) group (72.3 mg/dL) (P < 0.001). Serum IgM levels were significantly associated with sex. Serum IgM levels were positively correlated with traditional CAD risk factors such as TG, TC and LDL-C (P < 0.05), and negatively associated with the number of obstructed vessels, the number of affected areas, and Gensini scores. After adjusting for age, sex, smoking status, hypertension, dyslipidaemia, diabetes, stroke, and statin use history, a high IgM level was independently negatively associated with the severity of CAD expressed by the Gensini score. Conclusion We determined that serum IgM was independently negatively associated with the severity of CAD diagnosed by angiography in Chinese adults.
Collapse
Affiliation(s)
- Yanan Zhang
- The Affiliated Hospital of Qingdao University, Qing Dao, Shan Dong, China
| | - Xi Qi
- Beijing Hospital, Beijing, China
| | | | | | | | | | | | - Fusui Ji
- Beijing Hospital, Beijing, China
| | - Jun Dong
- Beijing Hospital, Beijing, China
| | - Xue Yu
- Beijing Hospital, Beijing, China
| |
Collapse
|
|
12
|
Shahjahan, Dey JK, Dey SK. Translational bioinformatics approach to combat cardiovascular disease and cancers. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 139:221-261. [PMID: 38448136 DOI: 10.1016/bs.apcsb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2024]
Abstract
Bioinformatics is an interconnected subject of science dealing with diverse fields including biology, chemistry, physics, statistics, mathematics, and computer science as the key fields to answer complicated physiological problems. Key intention of bioinformatics is to store, analyze, organize, and retrieve essential information about genome, proteome, transcriptome, metabolome, as well as organisms to investigate the biological system along with its dynamics, if any. The outcome of bioinformatics depends on the type, quantity, and quality of the raw data provided and the algorithm employed to analyze the same. Despite several approved medicines available, cardiovascular disorders (CVDs) and cancers comprises of the two leading causes of human deaths. Understanding the unknown facts of both these non-communicable disorders is inevitable to discover new pathways, find new drug targets, and eventually newer drugs to combat them successfully. Since, all these goals involve complex investigation and handling of various types of macro- and small- molecules of the human body, bioinformatics plays a key role in such processes. Results from such investigation has direct human application and thus we call this filed as translational bioinformatics. Current book chapter thus deals with diverse scope and applications of this translational bioinformatics to find cure, diagnosis, and understanding the mechanisms of CVDs and cancers. Developing complex yet small or long algorithms to address such problems is very common in translational bioinformatics. Structure-based drug discovery or AI-guided invention of novel antibodies that too with super-high accuracy, speed, and involvement of considerably low amount of investment are some of the astonishing features of the translational bioinformatics and its applications in the fields of CVDs and cancers.
Collapse
Affiliation(s)
- Shahjahan
- Laboratory for Structural Biology of Membrane Proteins, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India
| | - Joy Kumar Dey
- Central Council for Research in Homoeopathy, Ministry of Ayush, Govt. of India, New Delhi, Delhi, India
| | - Sanjay Kumar Dey
- Laboratory for Structural Biology of Membrane Proteins, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
| |
Collapse
|
|
13
|
Zhang Y, Jiang Y, Zou Y, Fan Y, Feng P, Fu X, Li K, Zhang J, Dong Y, Yan S, Zhang Y. Peripheral blood CD19 positive B lymphocytes increase after ischemic stroke and correlate with carotid atherosclerosis. Front Neurol 2023; 14:1308041. [PMID: 38221996 PMCID: PMC10784375 DOI: 10.3389/fneur.2023.1308041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 12/01/2023] [Indexed: 01/16/2024] Open
Abstract
Introduction Atherosclerosis is the primary pathological basis of ischemic stroke, and dyslipidemia is one of its major etiological factors. Acute ischemic stroke patients exhibit imbalances in lymphocyte subpopulations, yet the correlation between these dynamic changes in lymphocyte subpopulations and lipid metabolism disorders, as well as carotid atherosclerosis in stroke patients remains poorly understood. Methods We retrospectively analyzed the demographic data, risk factors of cerebrovascular disease, laboratory examination (lymphocyte subsets, lipid indexes, etc.), clinical features and c;/]-sity from December 2017 to September 2019 and non-stroke patients with dizziness/vertigo during the same period. Results The results showed that peripheral B lymphocyte proportions are elevated in acute ischemic stroke patients compared with those of the control group (13.6 ± 5.3 vs. 11.7 ± 4.4%, p = 0.006). Higher B lymphocyte proportions are associated with concurrent dyslipidemia, increased levels of vascular risk factors including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C), as well as decreased levels of the protective factor high-density lipoprotein cholesterol (HDL-C). Elevated B lymphocyte proportions are independently correlated with carotid atherosclerosis in stroke patients. Discussion We found CD19 positive B Lymphocytes increase after ischemic stroke and correlate with Carotid Atherosclerosis. Lymphocyte subpopulations should be highlighted in stroke patients.
Collapse
Affiliation(s)
- Yuhua Zhang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yu Jiang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yutian Zou
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Department of Neurology, Afflliated Changshu Hospital of Nantong University, Changshu, China
| | - Yinyin Fan
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Ping Feng
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiang Fu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Keru Li
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Jinru Zhang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yunlei Dong
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Shuying Yan
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yanlin Zhang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, China
| |
Collapse
|
|
14
|
Gerasimova EV, Shayakhmetova RU, Gerasimova DA, Popkova TV, Ananyeva LP. Systemic Sclerosis and Atherosclerosis: Potential Cellular Biomarkers and Mechanisms. Front Biosci (Schol Ed) 2023; 15:16. [PMID: 38163957 DOI: 10.31083/j.fbs1504016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 11/29/2023] [Accepted: 12/12/2023] [Indexed: 01/03/2024]
Abstract
Systemic sclerosis (SSc) is a rare systemic autoimmune disease of unknown etiology, which is characterized by endothelial dysfunction, pathologic vasculopathy, and increased tissue fibrosis. Traditionally, SSc has been regarded as a prototypical fibrotic disease in the family of systemic autoimmune diseases. Traditionally, emphasis has been placed on the three components of the pathogenesis of SSc: vascular, immune, and mesenchymal. Microvascular lesions, including endothelial dysfunction and smooth muscle cell migration into the intima of vessels in SSc, resemble the atherosclerotic process. Although microvascular disease is a hallmark of SSc, understanding the role of atherosclerotic vascular lesions in patients with SSc remains limited. It is still unknown whether the increased cardiovascular risk in SSc is related to specific cardiac complications (such as myocardial fibrosis) or the accelerated development of atherosclerosis. Different immune cell types appear to be involved in the immunopathogenesis of SSc via the activation of other immune cells, fibrosis, or vascular damage. Macrophages, B cells, T cells, dendritic cells, neutrophils, and endothelial cells have been reported to play the most important role in the pathogenesis of SSc and atherosclerosis. In our article, we reviewed the most significant and recent studies on the pathogenetic links between the development of SSc and the atherosclerotic process.
Collapse
Affiliation(s)
- Elena V Gerasimova
- Department of Systemic Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, 115522 Moscow, Russian Federation
| | - Rushana U Shayakhmetova
- Department of Systemic Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, 115522 Moscow, Russian Federation
| | - Daria A Gerasimova
- Department of Organization and Economics of Pharmacy, Federal State Autonomous Educational Institution of Higher Education I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 119991 Moscow, Russian Federation
| | - Tatiana V Popkova
- Department of Systemic Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, 115522 Moscow, Russian Federation
| | - Lidia P Ananyeva
- Department of Systemic Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, 115522 Moscow, Russian Federation
| |
Collapse
|
|
15
|
Malinowski D, Bochniak O, Luterek-Puszyńska K, Puszyński M, Pawlik A. Genetic Risk Factors Related to Coronary Artery Disease and Role of Transforming Growth Factor Beta 1 Polymorphisms. Genes (Basel) 2023; 14:1425. [PMID: 37510329 PMCID: PMC10379139 DOI: 10.3390/genes14071425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/28/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
Coronary artery disease (CAD) is one of the leading causes of mortality globally and has long been known to be heritable; however, the specific genetic factors involved have yet to be identified. Recent advances have started to unravel the genetic architecture of this disease and set high expectations about the future use of novel susceptibility variants for its prevention, diagnosis, and treatment. In the past decade, there has been major progress in this area. New tools, like common variant association studies, genome-wide association studies, meta-analyses, and genetic risk scores, allow a better understanding of the genetic risk factors driving CAD. In recent years, researchers have conducted further studies that confirmed the role of numerous genetic factors in the development of CAD. These include genes that affect lipid and carbohydrate metabolism, regulate the function of the endothelium and vascular smooth muscles, influence the coagulation system, or affect the immune system. Many CAD-associated single-nucleotide polymorphisms have been identified, although many of their functions are largely unknown. The inflammatory process that occurs in the coronary vessels is very important in the development of CAD. One important mediator of inflammation is TGFβ1. TGFβ1 plays an important role in the processes leading to CAD, such as by stimulating macrophage and fibroblast chemotaxis, as well as increasing extracellular matrix synthesis. This review discusses the genetic risk factors related to the development of CAD, with a particular focus on polymorphisms of the transforming growth factor β (TGFβ) gene and its receptor.
Collapse
Affiliation(s)
- Damian Malinowski
- Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Oliwia Bochniak
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Katarzyna Luterek-Puszyńska
- Department of Urology and Oncological Urology, Regional Specialist Hospital in Szczecin, 71-455 Szczecin, Poland; (K.L.-P.); (M.P.)
| | - Michał Puszyński
- Department of Urology and Oncological Urology, Regional Specialist Hospital in Szczecin, 71-455 Szczecin, Poland; (K.L.-P.); (M.P.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| |
Collapse
|
|
16
|
McCaffrey TA, Toma I, Yang Z, Katz R, Reiner J, Mazhari R, Shah P, Falk Z, Wargowsky R, Goldman J, Jones D, Shtokalo D, Antonets D, Jepson T, Fetisova A, Jaatinen K, Ree N, Ri M. RNAseq profiling of blood from patients with coronary artery disease: Signature of a T cell imbalance. JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY PLUS 2023; 4:100033. [PMID: 37303712 PMCID: PMC10256136 DOI: 10.1016/j.jmccpl.2023.100033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Background Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography either by invasive catheterization (ICA) or computed tomography (CTA). Prior studies employed single-molecule, amplification-independent RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. The present studies employed Illumina RNAseq and network co-expression analysis to identify systematic changes underlying CAD. Methods Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by Illumina total RNA sequencing (RNAseq) to identify transcripts associated with CAD in 177 patients presenting for elective invasive coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs) and to identify patterns of changes through whole genome co-expression network analysis (WGCNA). Results The correlation between Illumina amplified RNAseq and the prior SeqLL unamplified RNAseq was quite strong (r = 0.87), but there was only 9 % overlap in the DEGs identified. Consistent with the prior RNAseq, the majority (93 %) of DEGs were down-regulated ~1.7-fold in patients with moderate to severe CAD (>20 % stenosis). DEGs were predominantly related to T cells, consistent with known reductions in Tregs in CAD. Network analysis did not identify pre-existing modules with a strong association with CAD, but patterns of T cell dysregulation were evident. DEGs were enriched for transcripts associated with ciliary and synaptic transcripts, consistent with changes in the immune synapse of developing T cells. Conclusions These studies confirm and extend a novel mRNA signature of a Treg-like defect in CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.
Collapse
Affiliation(s)
- Timothy A. McCaffrey
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
- The St. Laurent Institute, 317 New Boston Street, Woburn, MA 01801, United States of America
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
- True Bearing Diagnostics, 2450 Virginia Avenue, Washington, DC 20037, United States of America
| | - Ian Toma
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
- Department of Clinical Research and Leadership, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
- True Bearing Diagnostics, 2450 Virginia Avenue, Washington, DC 20037, United States of America
| | - Zhaoqing Yang
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Richard Katz
- Department of Medicine, Division of Cardiology, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Jonathan Reiner
- Department of Medicine, Division of Cardiology, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Ramesh Mazhari
- Department of Medicine, Division of Cardiology, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Palak Shah
- INOVA Heart and Vascular Institute, 3300 Gallows Road, Fairfax, VA 22042, United States of America
| | - Zachary Falk
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Richard Wargowsky
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Jennifer Goldman
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Dan Jones
- SeqLL, Inc., 3 Federal Street, Billerica, MA 01821, United States of America
| | - Dmitry Shtokalo
- The St. Laurent Institute, 317 New Boston Street, Woburn, MA 01801, United States of America
- A.P. Ershov Institute of Informatics Systems SB RAS, 6, Acad. Lavrentyeva Ave, Novosibirsk 630090, Russia
| | - Denis Antonets
- The St. Laurent Institute, 317 New Boston Street, Woburn, MA 01801, United States of America
| | - Tisha Jepson
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
- The St. Laurent Institute, 317 New Boston Street, Woburn, MA 01801, United States of America
- True Bearing Diagnostics, 2450 Virginia Avenue, Washington, DC 20037, United States of America
| | - Anastasia Fetisova
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Kevin Jaatinen
- Department of Medicine, Division of Genomic Medicine, The George Washington University, 2300 I Street NW, Washington, DC 20037, United States of America
| | - Natalia Ree
- Center for Mitochondrial Functional Genomics, Institute of Living Systems, Immanuel Kant Baltic Federal University, Kalingrad 236040, Russia
| | - Maxim Ri
- The St. Laurent Institute, 317 New Boston Street, Woburn, MA 01801, United States of America
- A.P. Ershov Institute of Informatics Systems SB RAS, 6, Acad. Lavrentyeva Ave, Novosibirsk 630090, Russia
| |
Collapse
|
|
17
|
Walker CK, Greathouse KM, Tuscher JJ, Dammer EB, Weber AJ, Liu E, Curtis KA, Boros BD, Freeman CD, Seo JV, Ramdas R, Hurst C, Duong DM, Gearing M, Murchison CF, Day JJ, Seyfried NT, Herskowitz JH. Cross-Platform Synaptic Network Analysis of Human Entorhinal Cortex Identifies TWF2 as a Modulator of Dendritic Spine Length. J Neurosci 2023; 43:3764-3785. [PMID: 37055180 PMCID: PMC10198456 DOI: 10.1523/jneurosci.2102-22.2023] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 03/17/2023] [Accepted: 04/04/2023] [Indexed: 04/15/2023] Open
Abstract
Proteomic studies using postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer's disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex (EC) of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry (MS) data (n = 2260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (BA28; n = 58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients.SIGNIFICANCE STATEMENT Proteomic studies can yield vast lists of molecules that are altered under various experimental or disease conditions. Here, we provide a blueprint to facilitate mechanistic validation of protein targets from human brain proteomic datasets. We conducted a proteomic analysis of human entorhinal cortex (EC) samples spanning cognitively normal and Alzheimer's disease (AD) cases with a comparison of dendritic spine morphology in the same samples. Network integration of proteomics with dendritic spine measurements allowed for unbiased discovery of Twinfilin-2 (TWF2) as a regulator of dendritic spine length. A proof-of-concept experiment in cultured neurons demonstrated that altering Twinfilin-2 protein level induced corresponding changes in dendritic spine length, thus providing experimental validation for the computational framework.
Collapse
Affiliation(s)
- Courtney K Walker
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Kelsey M Greathouse
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jennifer J Tuscher
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Eric B Dammer
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Audrey J Weber
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Evan Liu
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Kendall A Curtis
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Benjamin D Boros
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Cameron D Freeman
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jung Vin Seo
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Raksha Ramdas
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Cheyenne Hurst
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Duc M Duong
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Marla Gearing
- Department of Pathology and Laboratory Medicine and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Charles F Murchison
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Jeremy J Day
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294
| | - Nicholas T Seyfried
- Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Jeremy H Herskowitz
- Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama 35294
| |
Collapse
|
|
18
|
Atzeni F, Maiani S, Corda M, Rodríguez-Carrio J. Diagnosis and management of cardiovascular risk in rheumatoid arthritis: main challenges and research agenda. Expert Rev Clin Immunol 2023; 19:279-292. [PMID: 36651086 DOI: 10.1080/1744666x.2023.2170351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Rheumatoid arthritis (RA) exhibit a cardiovascular (CV) risk that is 1.5-2.0 times higher compared to the general population. This CV risk excess is likely caused by the involvement of chronic inflammation and immune dysregulation. Therefore, conventional algorithms and imaging techniques fail to fully account for this risk excess and provide a suboptimal risk stratification, hence limiting clinical management in this setting. AREAS COVERED Compelling evidence has suggested a role for adaptations of conventional algorithms (Framingham, SCORE, AHA, etc) or the development of RA-specific algorithms, as well as the use of a number of several, noninvasive imaging techniques to improve CV risk assessment in RA populations. Similarly, in-depth analyses of atherosclerosis pathogenesis in RA patients have shed new light into a plethora of soluble biomarkers (such as inflammatory cytokines, vascular remodeling mediators or autoantibodies) that may provide incremental value for CV risk stratification. EXPERT OPINION Extensive research has demonstrated a lack of performance of chart adaptations in capturing real CV risk in RA population, as well as for RA-specific algorithms. Similarly, limitations have been detected in the use of soluble mediators. The development of a novel, RA-specific algorithm including classical and non-traditional risk factors may be advisable.
Collapse
Affiliation(s)
- Fabiola Atzeni
- Rheumatology Unit, Department of Experimental and Internal Medicine, University of Messina, Messina, Italy
| | - Silvia Maiani
- Clinical Cardiology, Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy
| | - Marco Corda
- S.C. Cardiologia UTIC, ARNAS, G.Brotzu, Cagliari, Italy
| | - Javier Rodríguez-Carrio
- Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.,Area of Metabolism, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| |
Collapse
|
|
19
|
Abdallah HY, Fareed A, Abdelmaogood AKK, Allam S, Abdelgawad M, Deen LATE. Introducing Circulating Vasculature-Related Transcripts as Biomarkers in Coronary Artery Disease. Mol Diagn Ther 2023; 27:243-259. [PMID: 36538237 PMCID: PMC10008268 DOI: 10.1007/s40291-022-00622-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Atherosclerotic plaque is considered the hallmark of atherosclerotic lesions in coronary atherosclerosis (CAS), the primary pathogenesis in coronary artery disease (CAD), which develops and progresses through a complex interplay between immune cells, vascular cells, and endothelial shear stresses. Early diagnosis of CAS is critical for avoiding plaque rupture and sudden death. Therefore, identifying new CAD biomarkers linked to vessel wall functions, such as RNA molecules with their distinct signature, is a promising development for these patients. With this rationale, the present study investigated the expression level of the vascular-related RNA transcripts (lncRNA ANRIL, miRNA-126-5p, CDK4, CDK6, TGF-β, E-cadherin, and TNF-α) implicated in the cellular vascular function, proliferation, and inflammatory processes. METHODS A case-control study design with a total of 180 subjects classified participants into two groups; CAD and control groups. The relative expression levels of the seven transcripts under study-selected using online bioinformatics tools and current literature-were assessed in the plasma of all study participants using RT-qPCR. Their predictive significance testing, scoring of disease prioritization, enrichment analysis, and the miRNA-mRNA regulatory network was investigated. RESULTS The relative expression levels of all seven of the circulating vascular-related transcripts under study were statistically significant between CAD patients and controls. Receiver operating characteristic (ROC) analysis results indicated the statistical significance of all the transcripts under study with CDK4 showing the highest area under the curve (AUC) equivalent to 0.91, followed by E-cadherin (0.90), miRNA-126-5p (0.83), ANRIL (0.82), TNF-α (0.63), TGF-β (0.62), and CDK6 (0.59), in descending order. A strong association was detected between most of the transcripts studied in CAD patients with a significant Spearman's correlation coefficient with a two-tailed significance of p < 0.001. Network analysis revealed a strong relationship between the five circulating vasculature transcripts studied and their target miRNAs and miR-126-5p, but not for ANRIL. CONCLUSION The seven circulating vascular-related RNA transcripts under study could serve as potential CAD biomarkers, reflecting the cellular vascular function, proliferation, and inflammatory processes in CAD patients. Therefore, blood transcriptome analysis opens new frontiers for the non-invasive diagnosis of CAD.
Collapse
Affiliation(s)
- Hoda Y Abdallah
- Medical Genetics Unit, Department of Histology and Cell Biology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt. .,Center of Excellence in Molecular and Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt.
| | - Ahmed Fareed
- Department of Cardiology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Asmaa K K Abdelmaogood
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Sahar Allam
- Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mai Abdelgawad
- Biotechnology and Life Sciences Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, Beni-Suef, Egypt
| | - Loaa A Tag El Deen
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| |
Collapse
|
|
20
|
Wang Z, Wang Y, Cui Y, Chen Z, Yi L, Zhu Z, Ni J, Du R, Wang X, Zhu J, Ding F, Quan W, Zhang R, Hu J, Yan X. Association of Serum BAFF Levels with Cardiovascular Events in ST-Segment Elevation Myocardial Infarction. J Clin Med 2023; 12:jcm12041692. [PMID: 36836225 PMCID: PMC9964977 DOI: 10.3390/jcm12041692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/12/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
OBJECTIVES The B cell activating factor (BAFF) is a B cell survival factor involved in atherosclerosis and ischemia-reperfusion (IR) injury. This study sought to investigate whether BAFF is a potential predictor of poor outcomes in patients with ST-segment elevation myocardial infarction (STEMI). METHODS We prospectively enrolled 299 patients with STEMI, and serum levels of BAFF were measured. All subjects were followed for three years. The primary endpoint was major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal reinfarction, hospitalization for heart failure (HF), and stroke. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of BAFF for MACEs. RESULTS In multivariate analysis, BAFF was independently associated with risk of MACEs (adjusted HR 1.525, 95% CI 1.085-2.145; p = 0.015) and cardiovascular death (adjusted hazard ratio [HR] 3.632, 95% confidence interval [CI] 1.132-11.650, p = 0.030) after adjustment for traditional risk factors. Kaplan-Meier survival curves demonstrated that patients with BAFF levels above the cut-off value (1.46 ng/mL) were more likely to have MACEs (log-rank p < 0.0001) and cardiovascular death (log-rank p < 0.0001). In subgroup analysis, the impact of high BAFF on MACEs development was stronger in patients without dyslipidemia. Furthermore, the C-statistic and Integrated Discrimination Improvement (IDI) values for MACEs were improved with BAFF as an independent risk factor or when combined with cardiac troponin I. CONCLUSIONS This study suggests that higher BAFF levels in the acute phase are an independent predictor of the incidence of MACEs in patients with STEMI.
Collapse
Affiliation(s)
- Ziyang Wang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yueying Wang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yuke Cui
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhiyong Chen
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lei Yi
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhengbin Zhu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jingwei Ni
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Run Du
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xiaoqun Wang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Jinzhou Zhu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Fenghua Ding
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Weiwei Quan
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ruiyan Zhang
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Correspondence: (R.Z.); (J.H.); (X.Y.); Tel./Fax: +86-21-6445-7177 (R.Z. & J.H. & X.Y.)
| | - Jian Hu
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Correspondence: (R.Z.); (J.H.); (X.Y.); Tel./Fax: +86-21-6445-7177 (R.Z. & J.H. & X.Y.)
| | - Xiaoxiang Yan
- Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Institute of Cardiovascular Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Correspondence: (R.Z.); (J.H.); (X.Y.); Tel./Fax: +86-21-6445-7177 (R.Z. & J.H. & X.Y.)
| |
Collapse
|
|
21
|
Ren H, Zhu B, An Y, Xie F, Wang Y, Tan Y. Immune communication between the intestinal microbiota and the cardiovascular system. Immunol Lett 2023; 254:13-20. [PMID: 36693435 DOI: 10.1016/j.imlet.2023.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/27/2022] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
The intestine hosts a large number of microbial communities. Recent studies have shown that gut microbiota-mediated immune responses play a vital role in developing cardiovascular diseases (CVD). Immune cells are extensively infiltrated in the gut and heart tissues, such as T cells, B cells, and macrophages. They play a crucial role in the crosstalk between the heart and gut microbiota. And the microbiota influences the bidirectional function of immune cells in CVD such as myocardial infarction and atherosclerosis, including through metabolites. The mapping of immune cell-mediated immune networks in the heart and gut provides us with new targets for treating CVD. This review discusses the role of immune cells in gut microbiota and cardiac communication during health and CVD.
Collapse
Affiliation(s)
- Hao Ren
- Department of Medical Microbiology, Central South University Changsha, Hunan Provinces, China
| | - Botao Zhu
- Department of Medical Microbiology, Central South University Changsha, Hunan Provinces, China
| | - Yuze An
- Department of Medical Microbiology, Central South University Changsha, Hunan Provinces, China
| | - Feng Xie
- Department of Medical Microbiology, Central South University Changsha, Hunan Provinces, China
| | - Yichuan Wang
- Department of Medical Microbiology, Central South University Changsha, Hunan Provinces, China
| | - Yurong Tan
- Department of Medical Microbiology, Central South University Changsha, Hunan Provinces, China.
| |
Collapse
|
|
22
|
Ma J, Huang A, Yan K, Li Y, Sun X, Joehanes R, Huan T, Levy D, Liu C. Blood transcriptomic biomarkers of alcohol consumption and cardiovascular disease risk factors: the Framingham Heart Study. Hum Mol Genet 2023; 32:649-658. [PMID: 36130209 PMCID: PMC9896471 DOI: 10.1093/hmg/ddac237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 08/19/2022] [Accepted: 09/15/2022] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The relations of alcohol consumption and gene expression remain to be elucidated. MATERIALS AND METHODS We examined cross-sectional associations between alcohol consumption and whole blood derived gene expression levels and between alcohol-associated genes and obesity, hypertension, and diabetes in 5531 Framingham Heart Study (FHS) participants. RESULTS We identified 25 alcohol-associated genes. We further showed cross-sectional associations of 16 alcohol-associated genes with obesity, nine genes with hypertension, and eight genes with diabetes at P < 0.002. For example, we observed decreased expression of PROK2 (β = -0.0018; 95%CI: -0.0021, -0.0007; P = 6.5e - 5) and PAX5 (β = -0.0014; 95%CI: -0.0021, -0.0007; P = 6.5e - 5) per 1 g/day increase in alcohol consumption. Consistent with our previous observation on the inverse association of alcohol consumption with obesity and positive association of alcohol consumption with hypertension, we found that PROK2 was positively associated with obesity (OR = 1.42; 95%CI: 1.17, 1.72; P = 4.5e - 4) and PAX5 was negatively associated with hypertension (OR = 0.73; 95%CI: 0.59, 0.89; P = 1.6e - 3). We also observed that alcohol consumption was positively associated with expression of ABCA13 (β = 0.0012; 95%CI: 0.0007, 0.0017; P = 1.3e - 6) and ABCA13 was positively associated with diabetes (OR = 2.57; 95%CI: 1.73, 3.84; P = 3.5e - 06); this finding, however, was inconsistent with our observation of an inverse association between alcohol consumption and diabetes. CONCLUSIONS We showed strong cross-sectional associations between alcohol consumption and expression levels of 25 genes in FHS participants. Nonetheless, complex relationships exist between alcohol-associated genes and CVD risk factors.
Collapse
Affiliation(s)
- Jiantao Ma
- Division of Nutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA 02111, USA
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Allen Huang
- Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02142, USA
| | - Kaiyu Yan
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
| | - Yi Li
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
| | - Xianbang Sun
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
| | - Roby Joehanes
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tianxiao Huan
- Department of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Daniel Levy
- Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Boston University’s and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
| | - Chunyu Liu
- Department of Biostatistics, Boston University, Boston, MA 02118, USA
- Boston University’s and National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
| |
Collapse
|
|
23
|
Xu P, Wang M, Sharma NK, Comeau ME, Wabitsch M, Langefeld CD, Civelek M, Zhang B, Das SK. Multi-omic integration reveals cell-type-specific regulatory networks of insulin resistance in distinct ancestry populations. Cell Syst 2023; 14:41-57.e8. [PMID: 36630956 PMCID: PMC9852073 DOI: 10.1016/j.cels.2022.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 09/26/2022] [Accepted: 12/13/2022] [Indexed: 01/12/2023]
Abstract
Our knowledge of the cell-type-specific mechanisms of insulin resistance remains limited. To dissect the cell-type-specific molecular signatures of insulin resistance, we performed a multiscale gene network analysis of adipose and muscle tissues in African and European ancestry populations. In adipose tissues, a comparative analysis revealed ethnically conserved cell-type signatures and two adipocyte subtype-enriched modules with opposite insulin sensitivity responses. The modules enriched for adipose stem and progenitor cells as well as immune cells showed negative correlations with insulin sensitivity. In muscle tissues, the modules enriched for stem cells and fibro-adipogenic progenitors responded to insulin sensitivity oppositely. The adipocyte and muscle fiber-enriched modules shared cellular-respiration-related genes but had tissue-specific rearrangements of gene regulations in response to insulin sensitivity. Integration of the gene co-expression and causal networks further pinpointed key drivers of insulin resistance. Together, this study revealed the cell-type-specific transcriptomic networks and signaling maps underlying insulin resistance in major glucose-responsive tissues. A record of this paper's transparent peer review process is included in the supplemental information.
Collapse
Affiliation(s)
- Peng Xu
- Department of Genetics & Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Minghui Wang
- Department of Genetics & Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Neeraj K Sharma
- Department of Internal Medicine, Section of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Mary E Comeau
- Department of Biostatistics and Data Science, Division of Public Health Sciences, and Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr. 24, D-89075 Ulm, Germany
| | - Carl D Langefeld
- Department of Biostatistics and Data Science, Division of Public Health Sciences, and Center for Precision Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Mete Civelek
- Center for Public Health Genomics, Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
| | - Bin Zhang
- Department of Genetics & Genomic Sciences, Mount Sinai Center for Transformative Disease Modeling, Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Swapan K Das
- Department of Internal Medicine, Section of Endocrinology and Metabolism, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
| |
Collapse
|
|
24
|
Biswas M, Suvarna R, Krishnan S V, Devasia T, Shenoy Belle V, Prabhu K. The mechanistic role of neutrophil lymphocyte ratio perturbations in the leading non communicable lifestyle diseases. F1000Res 2022; 11:960. [PMID: 36619602 PMCID: PMC9780608 DOI: 10.12688/f1000research.123245.1] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/08/2022] [Indexed: 01/13/2023] Open
Abstract
Inflammation plays a critical role in the development and progression of chronic diseases like type 2 diabetes mellitus, coronary artery disease, and chronic obstructive pulmonary disease. Inflammatory responses are indispensable for pathogen control and tissue repair, but they also cause collateral damage. A chronically activated immune system and the resultant immune dysregulation mediated inflammatory surge may cause multiple negative effects, requiring tight regulation and dampening of the immune response to minimize host injury. While chronic diseases are characterized by systemic inflammation, the mechanistic relationship of neutrophils and lymphocytes to inflammation and its correlation with the clinical outcomes is yet to be elucidated. The neutrophil to lymphocyte ratio (NLR) is an easy-to-measure laboratory marker used to assess systemic inflammation. Understanding the mechanisms of NLR perturbations in chronic diseases is crucial for risk stratification, early intervention, and finding novel therapeutic targets. We investigated the correlation between NLR and prevalent chronic conditions as a measure of systemic inflammation. In addition to predicting the risk of impending chronic conditions, NLR may also provide insight into their progression. This review summarizes the mechanisms of NLR perturbations at cellular and molecular levels, and the key inflammatory signaling pathways involved in the progression of chronic diseases. We have also explored preclinical studies investigating these pathways and the effect of quelling inflammation in chronic disease as reported by a few in vitro, in vivo studies, and clinical trials.
Collapse
Affiliation(s)
- Monalisa Biswas
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Renuka Suvarna
- Division of Ayurveda, Center for Integrative Medicine and Research, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Vimal Krishnan S
- Department of Emergency Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Tom Devasia
- Department of Cardiology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Vijetha Shenoy Belle
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India,
| | - Krishnananda Prabhu
- Department of Biochemistry, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India,
| |
Collapse
|
|
25
|
Li GQ, Liu XM, Liu BL, Zhong Y, Gu QW, Miao JJ, Wang J, Liu S, Mao XM. High triiodothyronine levels induce myocardial hypertrophy via BAFF overexpression. J Cell Mol Med 2022; 26:4453-4462. [PMID: 35808902 PMCID: PMC9357614 DOI: 10.1111/jcmm.17470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/18/2022] [Indexed: 11/27/2022] Open
Abstract
Activated B cells contribute to heart diseases, and inhibition of B‐cell activating factor (BAFF) expression is an effective therapeutic target for heart diseases. Whether activated B cells participate in the development and progression of hyperthyroid heart disease, and what induces B cells activation in hyperthyroidism are unknown. The present study aimed to determine the roles of BAFF overexpression induced by high concentrations of triiodothyronine (T3) in the pathogenesis of hyperthyroid heart disease. Female C57BL/6J mice were subcutaneously injected with T3 for 6 weeks, and BAFF expression was inhibited using shRNA. Protein and mRNA expression of BAFF in mouse heart tissues evaluated via immunohistochemistry, western blotting and polymerase chain reaction (PCR). Proportions of B cells in mouse cardiac tissue lymphocytes were quantified via flow cytometry. Morphology and left ventricle function were assessed using pathological sections and echocardiography, respectively. Here, we demonstrate that compared with the control group, the proportion of myocardial B cells was larger in the T3 group; immunohistochemistry, western blotting and PCR analyses revealed increased protein and mRNA expression levels of TNF‐α and BAFF in heart tissues of the T3 group. Compared with the normal controls group, in the T3 group, the diameter of myocardial cells and some echocardiographic values significantly increased and hypertrophy and structural disorder were noticeable. Our results revealed that elevated levels of circulating T3 can promote the expression of BAFF in myocardial cells and can lead to B‐cell activation, an elevated inflammatory response and ventricular remodelling.
Collapse
Affiliation(s)
- Guo-Qing Li
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiao-Mei Liu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bing-Li Liu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yi Zhong
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Qing-Wei Gu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jing-Jing Miao
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jie Wang
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Shu Liu
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiao-Ming Mao
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
26
|
Sonawane AR, Aikawa E, Aikawa M. Connections for Matters of the Heart: Network Medicine in Cardiovascular Diseases. Front Cardiovasc Med 2022; 9:873582. [PMID: 35665246 PMCID: PMC9160390 DOI: 10.3389/fcvm.2022.873582] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/19/2022] [Indexed: 01/18/2023] Open
Abstract
Cardiovascular diseases (CVD) are diverse disorders affecting the heart and vasculature in millions of people worldwide. Like other fields, CVD research has benefitted from the deluge of multiomics biomedical data. Current CVD research focuses on disease etiologies and mechanisms, identifying disease biomarkers, developing appropriate therapies and drugs, and stratifying patients into correct disease endotypes. Systems biology offers an alternative to traditional reductionist approaches and provides impetus for a comprehensive outlook toward diseases. As a focus area, network medicine specifically aids the translational aspect of in silico research. This review discusses the approach of network medicine and its application to CVD research.
Collapse
Affiliation(s)
- Abhijeet Rajendra Sonawane
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Elena Aikawa
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Masanori Aikawa
- Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
- Center for Excellence in Vascular Biology, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
27
|
Mallat Z, Binder CJ. The why and how of adaptive immune responses in ischemic cardiovascular disease. NATURE CARDIOVASCULAR RESEARCH 2022; 1:431-444. [PMID: 36382200 PMCID: PMC7613798 DOI: 10.1038/s44161-022-00049-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 03/10/2022] [Indexed: 02/02/2023]
Abstract
Atherosclerotic cardiovascular disease is a major cause of disability and death worldwide. Most therapeutic approaches target traditional risk factors but ignore the fundamental role of the immune system. This is a huge unmet need. Recent evidence indicates that reducing inflammation may limit cardiovascular events. However, the concomitant increase in the risk of lifethreatening infections is a major drawback. In this context, targeting adaptive immunity could constitute a highly effective and safer approach. In this Review, we address the why and how of the immuno-cardiovascular unit, in health and in atherosclerotic disease. We review and discuss fundamental mechanisms that ensure immune tolerance to cardiovascular tissue, and examine how their disruption promotes disease progression. We identify promising strategies to manipulate the adaptive immune system for patient benefit, including novel biologics and RNA-based vaccination strategies. Finally, we advocate for establishing a molecular classification of atherosclerosis as an important milestone in our quest to radically change the understanding and treatment of atherosclerotic disease.
Collapse
Affiliation(s)
- Ziad Mallat
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK
- Unversité de Paris, and INSERM U970, Paris Cardiovascular Research Centre, Paris, France
| | - Christoph J. Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
28
|
Smeets D, Gisterå A, Malin SG, Tsiantoulas D. The Spectrum of B Cell Functions in Atherosclerotic Cardiovascular Disease. Front Cardiovasc Med 2022; 9:864602. [PMID: 35497984 PMCID: PMC9051234 DOI: 10.3389/fcvm.2022.864602] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/02/2022] [Indexed: 01/03/2023] Open
Abstract
B cells are a core element of the pathophysiology of atherosclerotic cardiovascular disease (ASCVD). Multiple experimental and epidemiological studies have revealed both protective and deleterious functions of B cells in atherosclerotic plaque formation. The spearhead property of B cells that influences the development of atherosclerosis is their unique ability to produce and secrete high amounts of antigen-specific antibodies that can act at distant sites. Exposure to an atherogenic milieu impacts B cell homeostasis, cell differentiation and antibody production. However, it is not clear whether B cell responses in atherosclerosis are instructed by atherosclerosis-specific antigens (ASA). Dissecting the full spectrum of the B cell properties in atherosclerosis will pave the way for designing innovative therapies against the devastating consequences of ASCVD.
Collapse
Affiliation(s)
- Diede Smeets
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Anton Gisterå
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Stephen G. Malin
- Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | | |
Collapse
|
|
29
|
Castaneda AB, Petty LE, Scholz M, Jansen R, Weiss S, Zhang X, Schramm K, Beutner F, Kirsten H, Schminke U, Hwang SJ, Marzi C, Dhana K, Seldenrijk A, Krohn K, Homuth G, Wolf P, Peters MJ, Dörr M, Peters A, van Meurs JBJ, Uitterlinden AG, Kavousi M, Levy D, Herder C, van Grootheest G, Waldenberger M, Meisinger C, Rathmann W, Thiery J, Polak J, Koenig W, Seissler J, Bis JC, Franceshini N, Giambartolomei C, Hofman A, Franco OH, Penninx BWJH, Prokisch H, Völzke H, Loeffler M, O'Donnell CJ, Below JE, Dehghan A, de Vries PS. Associations of carotid intima media thickness with gene expression in whole blood and genetically predicted gene expression across 48 tissues. Hum Mol Genet 2022; 31:1171-1182. [PMID: 34788810 PMCID: PMC8976428 DOI: 10.1093/hmg/ddab236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/11/2021] [Accepted: 08/11/2021] [Indexed: 11/13/2022] Open
Abstract
Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.
Collapse
Affiliation(s)
- Andy B Castaneda
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Lauren E Petty
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Markus Scholz
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.,LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany
| | - Rick Jansen
- Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands
| | - Stefan Weiss
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.,DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany
| | - Xiaoling Zhang
- Department of Medicine, Boston University School of Medicine, Boston, MA, USA.,Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.,The Framingham Heart Study, Framingham, MA, USA
| | - Katharina Schramm
- Institute of Neurogenomics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,Institute of Human Genetics, Technical University Munich, Munich, Germany
| | | | - Holger Kirsten
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.,LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany
| | - Ulf Schminke
- Department of Neurology, University Medicine Greifswald, Greifswald, Germany
| | - Shih-Jen Hwang
- The Framingham Heart Study, Framingham, MA, USA.,Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA
| | - Carola Marzi
- Institute of Epidemiology, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Klodian Dhana
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Adrie Seldenrijk
- Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands
| | - Knut Krohn
- Interdisciplinary Center of Clinical Research, University of Leipzig, Leipzig, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Petra Wolf
- Institute of Neurogenomics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,Institute of Human Genetics, Technical University Munich, Munich, Germany
| | - Marjolein J Peters
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Marcus Dörr
- DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.,Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Joyce B J van Meurs
- Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - André G Uitterlinden
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Maryam Kavousi
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Daniel Levy
- The Framingham Heart Study, Framingham, MA, USA.,Population Sciences Branch, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD, USA
| | - Christian Herder
- Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.,German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany.,Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | | | - Melanie Waldenberger
- Institute of Epidemiology, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
| | - Christa Meisinger
- Institute of Epidemiology, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Augsburg, Germany
| | - Wolfgang Rathmann
- Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Joachim Thiery
- LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany.,Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University of Leipzig, Leipzig, Germany
| | - Joseph Polak
- Tufts University School of Medicine, Boston, MA, USA
| | - Wolfgang Koenig
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.,DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.,Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
| | - Jochen Seissler
- Diabetes Center, Diabetes Research Group, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität, Munich, Germany
| | - Joshua C Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Nora Franceshini
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
| | | | | | - Albert Hofman
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Oscar H Franco
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Institute of Social and Preventive Medicine, University of Bern, Switzerland
| | - Brenda W J H Penninx
- Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands
| | - Holger Prokisch
- Institute of Neurogenomics, Helmholz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.,Institute of Human Genetics, Technical University Munich, Munich, Germany
| | - Henry Völzke
- DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.,Institute of Community Medicine, University Medicine Greifswald, Greifswald, Germany
| | - Markus Loeffler
- Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.,LIFE Research Center of Civilization Diseases, University of Leipzig, Leipzig, Germany
| | - Christopher J O'Donnell
- The Framingham Heart Study, Framingham, MA, USA.,Cardiology Section, Department of Medicine, Boston Veteran's Administration Healthcare and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jennifer E Below
- Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Abbas Dehghan
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Epidemiology and Biostatistics, Imperial College London, London, UK.,MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, UK.,UK Dementia Research Institute at Imperial College London, Burlington Danes Building, Hammersmith Hospital, Du Cane Road, London W12 0NN UK
| | - Paul S de Vries
- Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.,Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
| |
Collapse
|
|
30
|
Yang H, Arif M, Yuan M, Li X, Shong K, Türkez H, Nielsen J, Uhlén M, Borén J, Zhang C, Mardinoglu A. A network-based approach reveals the dysregulated transcriptional regulation in non-alcoholic fatty liver disease. iScience 2021; 24:103222. [PMID: 34712920 PMCID: PMC8529555 DOI: 10.1016/j.isci.2021.103222] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/16/2021] [Accepted: 09/30/2021] [Indexed: 12/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. We performed network analysis to investigate the dysregulated biological processes in the disease progression and revealed the molecular mechanism underlying NAFLD. Based on network analysis, we identified a highly conserved disease-associated gene module across three different NAFLD cohorts and highlighted the predominant role of key transcriptional regulators associated with lipid and cholesterol metabolism. In addition, we revealed the detailed metabolic differences between heterogeneous NAFLD patients through integrative systems analysis of transcriptomic data and liver-specific genome-scale metabolic model. Furthermore, we identified transcription factors (TFs), including SREBF2, HNF4A, SREBF1, YY1, and KLF13, showing regulation of hepatic expression of genes in the NAFLD-associated modules and validated the TFs using data generated from a mouse NAFLD model. In conclusion, our integrative analysis facilitates the understanding of the regulatory mechanism of these perturbed TFs and their associated biological processes.
Disease-associated gene modules are conserved across multiple NAFLD cohorts The central genes in disease-associated modules are key enzymes in cholesterol synthesis YY1 and KLF13 are potential key transcriptional regulators of NAFLD development
Collapse
Affiliation(s)
- Hong Yang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Muhammad Arif
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Meng Yuan
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Koeun Shong
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Hasan Türkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Gothenburg, Sweden.,BioInnovation Institute, 2200 Copenhagen, Denmark
| | - Mathias Uhlén
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| |
Collapse
|
|
31
|
Xia N, Hasselwander S, Reifenberg G, Habermeier A, Closs EI, Mimmler M, Jung R, Karbach S, Lagrange J, Wenzel P, Daiber A, Münzel T, Hövelmeyer N, Waisman A, Li H. B Lymphocyte-Deficiency in Mice Causes Vascular Dysfunction by Inducing Neutrophilia. Biomedicines 2021; 9:biomedicines9111686. [PMID: 34829915 PMCID: PMC8615852 DOI: 10.3390/biomedicines9111686] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 10/17/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022] Open
Abstract
B lymphocytes have been implicated in the development of insulin resistance, atherosclerosis and certain types of hypertension. In contrast to these studies, which were performed under pathological conditions, the present study provides evidence for the protective effect of B lymphocytes in maintaining vascular homeostasis under physiological conditions. In young mice not exposed to any known risk factors, the lack of B cells led to massive endothelial dysfunction. The vascular dysfunction in B cell-deficient mice was associated with an increased number of neutrophils in the circulating blood. Neutrophil depletion in B cell-deficient mice resulted in the complete normalization of vascular function, indicating a causal role of neutrophilia. Moreover, vascular function in B cell-deficient mice could be restored by adoptive transfer of naive B-1 cells isolated from wild-type mice. Interestingly, B-1 cell transfer also reduced the number of neutrophils in the recipient mice, further supporting the involvement of neutrophils in the vascular pathology caused by B cell-deficiency. In conclusion, we report in the present study the hitherto undescribed role of B lymphocytes in regulating vascular function. B cell dysregulation may represent a crucial mechanism in vascular pathology.
Collapse
Affiliation(s)
- Ning Xia
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
| | - Solveig Hasselwander
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
| | - Gisela Reifenberg
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
| | - Alice Habermeier
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
| | - Ellen I. Closs
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
| | - Maximilian Mimmler
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
| | - Rebecca Jung
- Institute for Molecular Medicine, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (R.J.); (N.H.); (A.W.)
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (S.K.); (J.L.); (P.W.)
| | - Susanne Karbach
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (S.K.); (J.L.); (P.W.)
- Department of Cardiology, Cardiology 1, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (A.D.); (T.M.)
| | - Jérémy Lagrange
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (S.K.); (J.L.); (P.W.)
- Department of Cardiology, Cardiology 1, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (A.D.); (T.M.)
| | - Philip Wenzel
- Center for Thrombosis and Hemostasis, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (S.K.); (J.L.); (P.W.)
- Department of Cardiology, Cardiology 1, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (A.D.); (T.M.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, Cardiology 1, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (A.D.); (T.M.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology, Cardiology 1, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (A.D.); (T.M.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
| | - Nadine Hövelmeyer
- Institute for Molecular Medicine, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (R.J.); (N.H.); (A.W.)
- Research Center for Immunotherapy (FZI), Johannes Gutenberg University Medical Center, 55131 Mainz, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (R.J.); (N.H.); (A.W.)
- Research Center for Immunotherapy (FZI), Johannes Gutenberg University Medical Center, 55131 Mainz, Germany
| | - Huige Li
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131 Mainz, Germany; (N.X.); (S.H.); (G.R.); (A.H.); (E.I.C.); (M.M.)
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, 55131 Mainz, Germany
- Correspondence: ; Tel.: +49-(6131)-17-9348; Fax: +49-(6131)-17-9329
| |
Collapse
|
|
32
|
Westerlund AM, Hawe JS, Heinig M, Schunkert H. Risk Prediction of Cardiovascular Events by Exploration of Molecular Data with Explainable Artificial Intelligence. Int J Mol Sci 2021; 22:10291. [PMID: 34638627 PMCID: PMC8508897 DOI: 10.3390/ijms221910291] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/17/2021] [Accepted: 09/18/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases (CVD) annually take almost 18 million lives worldwide. Most lethal events occur months or years after the initial presentation. Indeed, many patients experience repeated complications or require multiple interventions (recurrent events). Apart from affecting the individual, this leads to high medical costs for society. Personalized treatment strategies aiming at prediction and prevention of recurrent events rely on early diagnosis and precise prognosis. Complementing the traditional environmental and clinical risk factors, multi-omics data provide a holistic view of the patient and disease progression, enabling studies to probe novel angles in risk stratification. Specifically, predictive molecular markers allow insights into regulatory networks, pathways, and mechanisms underlying disease. Moreover, artificial intelligence (AI) represents a powerful, yet adaptive, framework able to recognize complex patterns in large-scale clinical and molecular data with the potential to improve risk prediction. Here, we review the most recent advances in risk prediction of recurrent cardiovascular events, and discuss the value of molecular data and biomarkers for understanding patient risk in a systems biology context. Finally, we introduce explainable AI which may improve clinical decision systems by making predictions transparent to the medical practitioner.
Collapse
Affiliation(s)
- Annie M. Westerlund
- Department of Cardiology, Deutsches Herzzentrum München, Technical University Munich, Lazarettstrasse 36, 80636 Munich, Germany; (A.M.W.); (J.S.H.)
- Institute of Computational Biology, HelmholtzZentrum München, Ingolstädter Landstrasse 1, 85764 Munich, Germany
| | - Johann S. Hawe
- Department of Cardiology, Deutsches Herzzentrum München, Technical University Munich, Lazarettstrasse 36, 80636 Munich, Germany; (A.M.W.); (J.S.H.)
| | - Matthias Heinig
- Institute of Computational Biology, HelmholtzZentrum München, Ingolstädter Landstrasse 1, 85764 Munich, Germany
- Department of Informatics, Technical University Munich, Boltzmannstrasse 3, 85748 Garching, Germany
| | - Heribert Schunkert
- Department of Cardiology, Deutsches Herzzentrum München, Technical University Munich, Lazarettstrasse 36, 80636 Munich, Germany; (A.M.W.); (J.S.H.)
- Deutsches Zentrum für Herz- und Kreislaufforschung (DZHK), Munich Heart Alliance, Biedersteiner Strasse 29, 80802 Munich, Germany
| |
Collapse
|
|
33
|
McCaffrey TA, Toma I, Yang Z, Katz R, Reiner J, Mazhari R, Shah P, Tackett M, Jones D, Jepson T, Falk Z, Wargodsky R, Shtakalo D, Antonets D, Ertle J, Kim JH, Lai Y, Arslan Z, Aledort E, Alfaraidy M, Laurent GS. RNA sequencing of blood in coronary artery disease: involvement of regulatory T cell imbalance. BMC Med Genomics 2021; 14:216. [PMID: 34479557 PMCID: PMC8414682 DOI: 10.1186/s12920-021-01062-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 08/19/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cardiovascular disease had a global prevalence of 523 million cases and 18.6 million deaths in 2019. The current standard for diagnosing coronary artery disease (CAD) is coronary angiography. Surprisingly, despite well-established clinical indications, up to 40% of the one million invasive cardiac catheterizations return a result of 'no blockage'. The present studies employed RNA sequencing of whole blood to identify an RNA signature in patients with angiographically confirmed CAD. METHODS Whole blood RNA was depleted of ribosomal RNA (rRNA) and analyzed by single-molecule sequencing of RNA (RNAseq) to identify transcripts associated with CAD (TRACs) in a discovery group of 96 patients presenting for elective coronary catheterization. The resulting transcript counts were compared between groups to identify differentially expressed genes (DEGs). RESULTS Surprisingly, 98% of DEGs/TRACs were down-regulated ~ 1.7-fold in patients with mild to severe CAD (> 20% stenosis). The TRACs were independent of comorbid risk factors for CAD, such as sex, hypertension, and smoking. Bioinformatic analysis identified an enrichment in transcripts such as FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A that are likely markers of regulatory T cells (Treg), consistent with known reductions in Tregs in CAD. A validation cohort of 80 patients confirmed the overall pattern (92% down-regulation) and supported many of the Treg-related changes. TRACs were enriched for transcripts associated with stress granules, which sequester RNAs, and ciliary and synaptic transcripts, possibly consistent with changes in the immune synapse of developing T cells. CONCLUSIONS These studies identify a novel mRNA signature of a Treg-like defect in CAD patients and provides a blueprint for a diagnostic test for CAD. The pattern of changes is consistent with stress-related changes in the maturation of T and Treg cells, possibly due to changes in the immune synapse.
Collapse
Affiliation(s)
- Timothy A McCaffrey
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA.
- The St. Laurent Institute, Vancouver, WA, USA.
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington, DC, 20037, USA.
- True Bearing Diagnostics, Washington, DC, 20037, USA.
| | - Ian Toma
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
- Department of Clinical Research and Leadership, The George Washington University, Washington, DC, 20037, USA
- True Bearing Diagnostics, Washington, DC, 20037, USA
| | - Zhaoquing Yang
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | - Richard Katz
- Division of Cardiology, Department of Medicine, The George Washington University , Washington, DC, 20037, USA
| | - Jonathan Reiner
- Division of Cardiology, Department of Medicine, The George Washington University , Washington, DC, 20037, USA
| | - Ramesh Mazhari
- Division of Cardiology, Department of Medicine, The George Washington University , Washington, DC, 20037, USA
| | - Palak Shah
- Inova Heart and Vascular Institute, Fairfax, VA, USA
| | | | | | - Tisha Jepson
- SeqLL, Inc., Woburn, MA, USA
- The St. Laurent Institute, Vancouver, WA, USA
- True Bearing Diagnostics, Washington, DC, 20037, USA
| | - Zachary Falk
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | - Richard Wargodsky
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | - Dmitry Shtakalo
- A.P. Ershov Institute of Informatics Systems SB RAS, 6, Acad. Lavrentjeva Ave, Novosibirsk, Russia, 630090
| | - Denis Antonets
- A.P. Ershov Institute of Informatics Systems SB RAS, 6, Acad. Lavrentjeva Ave, Novosibirsk, Russia, 630090
| | - Justin Ertle
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | - Ju H Kim
- Division of Cardiology, Department of Medicine, The George Washington University , Washington, DC, 20037, USA
| | - Yinglei Lai
- Department of Statistics, Biostatistics Center, The George Washington University, Washington, DC, 20037, USA
| | - Zeynep Arslan
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | - Emily Aledort
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | - Maha Alfaraidy
- Division of Genomic Medicine, Department of Medicine, The George Washington Medical Center, The George Washington University, 2300 I Street NW, Ross Hall 443A, Washington, DC, 20037, USA
| | | |
Collapse
|
|
34
|
Porsch F, Mallat Z, Binder CJ. Humoral immunity in atherosclerosis and myocardial infarction: from B cells to antibodies. Cardiovasc Res 2021; 117:2544-2562. [PMID: 34450620 DOI: 10.1093/cvr/cvab285] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/30/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Immune mechanisms are critically involved in the pathogenesis of atherosclerosis and its clinical manifestations. Associations of specific antibody levels and defined B cell subsets with cardiovascular disease activity in humans as well as mounting evidence from preclinical models demonstrate a role of B cells and humoral immunity in atherosclerotic cardiovascular disease. These include all aspects of B cell immunity, the generation of antigen-specific antibodies, antigen presentation and co-stimulation of T cells, as well as production of cytokines. Through their impact on adaptive and innate immune responses and the regulation of many other immune cells, B cells mediate both protective and detrimental effects in cardiovascular disease. Several antigens derived from (oxidised) lipoproteins, the vascular wall and classical autoantigens have been identified. The unique antibody responses they trigger and their relationship with atherosclerotic cardiovascular disease are reviewed. In particular, we focus on the different effector functions of specific IgM, IgG, and IgE antibodies and the cellular responses they trigger and highlight potential strategies to target B cell functions for therapy.
Collapse
Affiliation(s)
- Florentina Porsch
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Ziad Mallat
- Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom.,INSERM U970, Paris Cardiovascular Research Centre, Paris, France.,Unversité Paris Descartes, Sorbonne Paris Cité, Paris France
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
35
|
Liang X, Wu T, Chen Q, Jiang J, Jiang Y, Ruan Y, Zhang H, Zhang S, Zhang C, Chen P, Lv Y, Xin J, Shi D, Chen X, Li J, Xu Y. Serum proteomics reveals disorder of lipoprotein metabolism in sepsis. Life Sci Alliance 2021; 4:4/10/e202101091. [PMID: 34429344 PMCID: PMC8385306 DOI: 10.26508/lsa.202101091] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022] Open
Abstract
This study illustrated that lipoprotein and lipid metabolism might play a significant role in patients with sepsis and that complement activation was significantly enriched in patients with sepsis-associated encephalopathy. Sepsis is defined as an organ dysfunction syndrome and it has high mortality worldwide. This study analysed the proteome of serum from patients with sepsis to characterize the pathological mechanism and pathways involved in sepsis. A total of 59 patients with sepsis were enrolled for quantitative proteomic analysis. Weighted gene co-expression network analysis (WGCNA) was performed to construct a co-expression network specific to sepsis. Key regulatory modules that were detected were highly correlated with sepsis patients and related to multiple functional groups, including plasma lipoprotein particle remodeling, inflammatory response, and wound healing. Complement activation was significantly associated with sepsis-associated encephalopathy. Triglyceride/cholesterol homeostasis was found to be related to sepsis-associated acute kidney injury. Twelve hub proteins were identified, which might be predictive biomarkers of sepsis. External validation of the hub proteins showed their significantly differential expression in sepsis patients. This study identified that plasma lipoprotein processes played a crucial role in sepsis patients, that complement activation contributed to sepsis-associated encephalopathy, and that triglyceride/cholesterol homeostasis was associated with sepsis-associated acute kidney injury.
Collapse
Affiliation(s)
- Xi Liang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Tianzhou Wu
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jing Jiang
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yongpo Jiang
- Department of Intensive Care Unit, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, China
| | - Yanyun Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Huaping Zhang
- Department of Intensive Care Unit, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Sheng Zhang
- Department of Intensive Care Unit, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Taizhou, China
| | - Chao Zhang
- Department of Intensive Care Unit, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, China
| | - Peng Chen
- Department of Intensive Care Unit, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, China
| | - Yuhang Lv
- Department of Intensive Care Unit, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jiaojiao Xin
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongyan Shi
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xin Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China .,Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Li
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China .,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yinghe Xu
- Department of Intensive Care Unit, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| |
Collapse
|
|
36
|
Muhammad K, Ayoub MA, Iratni R. Vascular Inflammation in Cardiovascular Disease: Is Immune System Protective or Bystander? Curr Pharm Des 2021; 27:2141-2150. [PMID: 33461451 DOI: 10.2174/1381612827666210118121952] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/15/2020] [Indexed: 11/22/2022]
Abstract
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. Chronic atherosclerosis induced vascular inflammation and perturbation of lipid metabolism is believed to be a major cause of CVD. Interplay of innate and adaptive Immune system has been interwined with various risk factors associated with the initiation and progression of atherosclerosis in CVD. A large body of evidence indicates a correlation between immunity and atherosclerosis. Retention of plasma lipoproteins in arterial subendothelial wall triggers the T helper type 1 (Th1) cells and monocyte-derived macrophages to form atherosclerotic plaques. In the present review, we will discuss the pathogenesis of CVD in relation to atherosclerosis with a particular focus on pro-atherogenic role of immune cells. Recent findings have also suggested anti-atherogenic roles of different B cell subsets. Therapeutic approaches to target atherosclerosis risk factors have reduced the mortality, but a need exists for the novel therapies to treat arterial vascular inflammation. These insights into the immune pathogenesis of atherosclerosis can lead to new targeted therapeutics to abate cardiovascular mortality and morbidity.
Collapse
Affiliation(s)
- Khalid Muhammad
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Mohammed A Ayoub
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Rabah Iratni
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| |
Collapse
|
|
37
|
Deroissart J, Porsch F, Koller T, Binder CJ. Anti-inflammatory and Immunomodulatory Therapies in Atherosclerosis. Handb Exp Pharmacol 2021; 270:359-404. [PMID: 34251531 DOI: 10.1007/164_2021_505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Hypercholesterolemia is a major risk factor in atherosclerosis development and lipid-lowering drugs (i.e., statins) remain the treatment of choice. Despite effective reduction of LDL cholesterol in patients, a residual cardiovascular risk persists in some individuals, highlighting the need for further therapeutic intervention. Recently, the CANTOS trial paved the way toward the development of specific therapies targeting inflammation, a key feature in atherosclerosis progression. The pre-existence of multiple drugs modulating both innate and adaptive immune responses has significantly accelerated the number of translational studies applying these drugs to atherosclerosis. Additional preclinical research has led to the discovery of new therapeutic targets, offering promising perspectives for the treatment and prevention of atherosclerosis. Currently, both drugs with selective targeting and broad unspecific anti-inflammatory effects have been tested. In this chapter, we aim to give an overview of current advances in immunomodulatory treatment approaches for atherosclerotic cardiovascular diseases.
Collapse
Affiliation(s)
- Justine Deroissart
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Florentina Porsch
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Thomas Koller
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
38
|
Kassiteridi C, Cole JE, Griseri T, Falck-Hansen M, Goddard ME, Seneviratne AN, Green PA, Park I, Shami AG, Pattarabanjird T, Upadhye A, Taylor AM, Handa A, Channon KM, Lutgens E, McNamara CA, Williams RO, Monaco C. CD200 Limits Monopoiesis and Monocyte Recruitment in Atherosclerosis. Circ Res 2021; 129:280-295. [PMID: 33975450 PMCID: PMC8260471 DOI: 10.1161/circresaha.119.316062] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 05/06/2021] [Accepted: 05/10/2021] [Indexed: 12/26/2022]
Abstract
[Figure: see text].
Collapse
MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Aorta/immunology
- Aorta/metabolism
- Aorta/pathology
- Aortic Diseases/genetics
- Aortic Diseases/immunology
- Aortic Diseases/metabolism
- Aortic Diseases/pathology
- Atherosclerosis/genetics
- Atherosclerosis/immunology
- Atherosclerosis/metabolism
- Atherosclerosis/pathology
- Cells, Cultured
- Chemotaxis, Leukocyte
- Coronary Artery Disease/diagnostic imaging
- Coronary Artery Disease/immunology
- Coronary Artery Disease/metabolism
- Disease Models, Animal
- Female
- Humans
- Leukopoiesis
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Membrane Glycoproteins/metabolism
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- Middle Aged
- Monocytes/immunology
- Monocytes/metabolism
- Orexin Receptors/metabolism
- Phosphorylation
- Plaque, Atherosclerotic
- STAT1 Transcription Factor/metabolism
- Signal Transduction
- Mice
Collapse
Affiliation(s)
- Christina Kassiteridi
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Jennifer E. Cole
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Thibault Griseri
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Mika Falck-Hansen
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Michael E. Goddard
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Anusha N. Seneviratne
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Patricia A. Green
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Inhye Park
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Annelie G. Shami
- Experimental Vascular Biology Division, Department of Medical Biochemistry, Amsterdam UMC, the Netherlands (A.G.S.,)
| | | | - Aditi Upadhye
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| | - Angela M. Taylor
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| | - Ashok Handa
- Nuffield Department of Surgical Sciences (A.H.), University of Oxford, UK
| | - Keith M. Channon
- Radcliffe Department of Medicine, RDM Cardiovascular Medicine (K.M.C.), University of Oxford, UK
| | - Esther Lutgens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany & German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L.)
| | - Coleen A. McNamara
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| | - Richard O. Williams
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
| | - Claudia Monaco
- Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (C.K., J.E.C., T.G., M.F.-H., M.E.G., A.N.S., P.A.G., I.P., R.O.W., C.A.M.), University of Oxford, UK
- Nuffield Department of Surgical Sciences (A.H.), University of Oxford, UK
- Radcliffe Department of Medicine, RDM Cardiovascular Medicine (K.M.C.), University of Oxford, UK
- Experimental Vascular Biology Division, Department of Medical Biochemistry, Amsterdam UMC, the Netherlands (A.G.S.,)
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, München, Germany & German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany (E.L.)
- Cardiovascular Research Center, University of Virginia (T.P., A.U., A.M.T., C.A.M.)
| |
Collapse
|
|
39
|
Pattarabanjird T, Li C, McNamara C. B Cells in Atherosclerosis: Mechanisms and Potential Clinical Applications. ACTA ACUST UNITED AC 2021; 6:546-563. [PMID: 34222726 PMCID: PMC8246059 DOI: 10.1016/j.jacbts.2021.01.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/05/2021] [Accepted: 01/05/2021] [Indexed: 12/17/2022]
Abstract
B cells regulate atherosclerotic plaque formation through production of antibodies and cytokines, and effects are subset specific (B1 and B2). Putative human atheroprotective B1 cells function similarly to murine B1 in their spontaneous IgM antibody production. However, marker strategies in identifying human and murine B1 are different. IgM antibody to oxidation specific epitopes produced by B1 cells associate with human coronary artery disease. Neoantigen immunization may be a promising strategy for atherosclerosis vaccine development, but further study to determine relevant antigens still need to be done. B-cell–targeted therapies, used in treating autoimmune diseases as well as lymphoid cancers, might have potential applications in treating cardiovascular diseases. Short- and long-term cardiovascular effects of these agents need to be assessed. Because atherosclerotic cardiovascular disease is a leading cause of death worldwide, understanding inflammatory processes underpinning its pathology is critical. B cells have been implicated as a key immune cell type in regulating atherosclerosis. B-cell effects, mediated by antibodies and cytokines, are subset specific. In this review, we focus on elaborating mechanisms underlying subtype-specific roles of B cells in atherosclerosis and discuss available human data implicating B cells in atherosclerosis. We further discuss potential B cell–linked therapeutic approaches, including immunization and B cell–targeted biologics. Given recent evidence strongly supporting a role for B cells in human atherosclerosis and the expansion of immunomodulatory agents that affect B-cell biology in clinical use and clinical trials for other disorders, it is important that the cardiovascular field be cognizant of potential beneficial or untoward effects of modulating B-cell activity on atherosclerosis.
Collapse
Key Words
- APRIL, A proliferation−inducing ligand
- ApoE, apolipoprotein E
- B-cell
- BAFF, B-cell–activating factor
- BAFFR, B-cell–activating factor receptor
- BCMA, B-cell maturation antigen
- BCR, B-cell receptor
- Breg, regulatory B cell
- CAD, coronary artery disease
- CTLA4, cytotoxic T-lymphocyte–associated protein 4
- CVD, cardiovascular disease
- CXCR4, C-X-C motif chemokine receptor 4
- GC, germinal center
- GITR, glucocorticoid-induced tumor necrosis factor receptor–related protein
- GITRL, glucocorticoid-induced tumor necrosis factor receptor–related protein ligand
- GM-CSF, granulocyte-macrophage colony–stimulating factor
- ICI, immune checkpoint inhibitor
- IFN, interferon
- IL, interleukin
- IVUS, intravascular ultrasound
- LDL, low-density lipoprotein
- LDLR, low-density lipoprotein receptor
- MDA-LDL, malondialdehyde-modified low-density lipoprotein
- MI, myocardial infarction
- OSE, oxidation-specific epitope
- OxLDL, oxidized low-density lipoprotein
- PC, phosphorylcholine
- PD-1, programmed cell death protein 1
- PD-L2, programmed death ligand 2
- PDL1, programmed death ligand 1
- RA, rheumatoid arthritis
- SLE, systemic lupus erythematosus
- TACI, transmembrane activator and CAML interactor
- TNF, tumor necrosis factor
- Treg, regulatory T cell
- atherosclerosis
- immunoglobulins
- mAb, monoclonal antibody
Collapse
Affiliation(s)
- Tanyaporn Pattarabanjird
- Cardiovascular Research Center, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.,Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA
| | - Cynthia Li
- Cardiovascular Research Center, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| | - Coleen McNamara
- Cardiovascular Research Center, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA.,Division of Cardiovascular Medicine, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
| |
Collapse
|
|
40
|
Joshi A, Rienks M, Theofilatos K, Mayr M. Systems biology in cardiovascular disease: a multiomics approach. Nat Rev Cardiol 2021; 18:313-330. [PMID: 33340009 DOI: 10.1038/s41569-020-00477-1] [Citation(s) in RCA: 131] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/02/2020] [Indexed: 12/13/2022]
Abstract
Omics techniques generate large, multidimensional data that are amenable to analysis by new informatics approaches alongside conventional statistical methods. Systems theories, including network analysis and machine learning, are well placed for analysing these data but must be applied with an understanding of the relevant biological and computational theories. Through applying these techniques to omics data, systems biology addresses the problems posed by the complex organization of biological processes. In this Review, we describe the techniques and sources of omics data, outline network theory, and highlight exemplars of novel approaches that combine gene regulatory and co-expression networks, proteomics, metabolomics, lipidomics and phenomics with informatics techniques to provide new insights into cardiovascular disease. The use of systems approaches will become necessary to integrate data from more than one omic technique. Although understanding the interactions between different omics data requires increasingly complex concepts and methods, we argue that hypothesis-driven investigations and independent validation must still accompany these novel systems biology approaches to realize their full potential.
Collapse
Affiliation(s)
- Abhishek Joshi
- King's British Heart Foundation Centre, King's College London, London, UK
- Bart's Heart Centre, St. Bartholomew's Hospital, London, UK
| | - Marieke Rienks
- King's British Heart Foundation Centre, King's College London, London, UK
| | | | - Manuel Mayr
- King's British Heart Foundation Centre, King's College London, London, UK.
| |
Collapse
|
|
41
|
Precision Medicine Approaches to Vascular Disease: JACC Focus Seminar 2/5. J Am Coll Cardiol 2021; 77:2531-2550. [PMID: 34016266 DOI: 10.1016/j.jacc.2021.04.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/16/2022]
Abstract
In this second of a 5-part Focus Seminar series, we focus on precision medicine in the context of vascular disease. The most common vascular disease worldwide is atherosclerosis, which is the primary cause of coronary artery disease, peripheral vascular disease, and a large proportion of strokes and other disorders. Atherosclerosis is a complex genetic disease that likely involves many hundreds to thousands of single nucleotide polymorphisms, each with a relatively modest effect for causing disease. Conversely, although less prevalent, there are many vascular disorders that typically involve only a single genetic change, but these changes can often have a profound effect that is sufficient to cause disease. These are termed "Mendelian vascular diseases," which include Marfan and Loeys-Dietz syndromes. Given the very different genetic basis of atherosclerosis versus Mendelian vascular diseases, this article was divided into 2 parts to cover the most promising precision medicine approaches for these disease types.
Collapse
|
|
42
|
Nipping Adipocyte Inflammation in the Bud. ACTA ACUST UNITED AC 2021; 3. [PMID: 33732506 PMCID: PMC7963359 DOI: 10.20900/immunometab20210012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Adipose tissue inflammation continues to represent a significant area of research in immunometabolism. We have identified a transcription factor, EBF1, which crucially regulates the expression of numerous inflammatory loci in adipocytes. However, EBF1 appears to do so without physically binding to these inflammatory genes. Our research is currently focused on understanding this discrepancy, and we believe that future findings could pave the road for drug development aimed to block adipose inflammation at its source.
Collapse
|
|
43
|
Yang Y, Xu X. Identification of key genes in coronary artery disease: an integrative approach based on weighted gene co-expression network analysis and their correlation with immune infiltration. Aging (Albany NY) 2021; 13:8306-8319. [PMID: 33686958 PMCID: PMC8034924 DOI: 10.18632/aging.202638] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 01/29/2021] [Indexed: 12/04/2022]
Abstract
This study aimed to identify key genes related to coronary artery disease (CAD) and its association with immune cells infiltration. GSE20680 and GSE20681 were downloaded from GEO. We identified red and pink modules in WGCNA analysis and found 104 genes in these two modules. Next, least absolute shrinkage and selection operator (LASSO) logistic regression was used to screen and verify the diagnostic markers of CAD. We identified ASCC2, LRRC18, and SLC25A37 as the key genes in CAD diagnosis. We further studied the immune cells infiltration in CAD patients with CIBERSORT, and the correlation between key genes and infiltrating immune cells was analyzed. We also found immune cells, including macrophages M0, mast cells resting and T cells CD8, were associated with ASCC2, LRRC18 and SLC25A37. Gene enrichment analysis indicated that these genes mainly enriched in apoptotic signaling pathway for biological pathway analysis, riboflavin metabolism for KEGG analysis. The diagnostic efficiency of these key genes measured by AUC in the training set, testing set and validation cohort was 0.92, 0.96 and 0.83, respectively. In conclusion, ASCC2, LRRC18 and SLC25A37 can be used as diagnostic markers of CAD, and immune cell infiltration plays an important role in the onset and development of CAD.
Collapse
Affiliation(s)
- Yang Yang
- Fourth Affiliated Hospital of China Medical University, Huanggu, Shenyang 110032, Liaoning, China
| | - Xiangshan Xu
- Fourth Affiliated Hospital of China Medical University, Huanggu, Shenyang 110032, Liaoning, China
| |
Collapse
|
|
44
|
Wang M, Li A, Sekiya M, Beckmann ND, Quan X, Schrode N, Fernando MB, Yu A, Zhu L, Cao J, Lyu L, Horgusluoglu E, Wang Q, Guo L, Wang YS, Neff R, Song WM, Wang E, Shen Q, Zhou X, Ming C, Ho SM, Vatansever S, Kaniskan HÜ, Jin J, Zhou MM, Ando K, Ho L, Slesinger PA, Yue Z, Zhu J, Katsel P, Gandy S, Ehrlich ME, Fossati V, Noggle S, Cai D, Haroutunian V, Iijima KM, Schadt E, Brennand KJ, Zhang B. Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease. Neuron 2021; 109:257-272.e14. [PMID: 33238137 PMCID: PMC7855384 DOI: 10.1016/j.neuron.2020.11.002] [Citation(s) in RCA: 109] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 09/16/2020] [Accepted: 10/30/2020] [Indexed: 01/11/2023]
Abstract
To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.
Collapse
Affiliation(s)
- Minghui Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,These authors contributed equally
| | - Aiqun Li
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,These authors contributed equally
| | - Michiko Sekiya
- Department of Alzheimer’s Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan 474-8511,Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan 467-8603,These authors contributed equally
| | - Noam D. Beckmann
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,These authors contributed equally
| | - Xiuming Quan
- Department of Alzheimer’s Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan 474-8511,These authors contributed equally
| | - Nadine Schrode
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Michael B. Fernando
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Alex Yu
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Li Zhu
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York NY 10029,Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York NY 10029,The New York Stem Cell Foundation Research Institute, New York, NY 10019
| | - Jiqing Cao
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York NY 10029,Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York NY 10029,The New York Stem Cell Foundation Research Institute, New York, NY 10019
| | - Liwei Lyu
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Emrin Horgusluoglu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Qian Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Lei Guo
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Yuan-shuo Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Ryan Neff
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Won-min Song
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Erming Wang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Qi Shen
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Xianxiao Zhou
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Chen Ming
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Seok-Man Ho
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Sezen Vatansever
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - H. Ümit Kaniskan
- Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY10029, United States
| | - Jian Jin
- Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY10029, United States.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY10029, United States
| | - Ming-Ming Zhou
- Department of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Kanae Ando
- Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan 192-0397
| | - Lap Ho
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Paul A. Slesinger
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA
| | - Zhenyu Yue
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York NY 10029
| | - Jun Zhu
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA
| | - Pavel Katsel
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA
| | - Sam Gandy
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Neurology, Icahn School of Medicine at Mount Sinai, New York NY 10029,Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York NY 10029
| | - Michelle E. Ehrlich
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York NY 10029,Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York NY 10029
| | - Valentina Fossati
- The New York Stem Cell Foundation Research Institute, New York, NY 10019
| | - Scott Noggle
- The New York Stem Cell Foundation Research Institute, New York, NY 10019
| | - Dongming Cai
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York NY 10029,Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York NY 10029,Neurology, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA
| | - Vahram Haroutunian
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York NY 10029,Psychiatry, JJ Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA
| | - Koichi M. Iijima
- Department of Alzheimer’s Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan 474-8511,Department of Experimental Gerontology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan 467-8603,Senior author
| | - Eric Schadt
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Senior author
| | - Kristen J. Brennand
- Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA,Senior author
| | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA,Senior author,Lead Contact,Correspondence: (B.Z.)
| |
Collapse
|
|
45
|
Adaptive Immune Responses in Human Atherosclerosis. Int J Mol Sci 2020; 21:ijms21239322. [PMID: 33297441 PMCID: PMC7731312 DOI: 10.3390/ijms21239322] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/27/2020] [Accepted: 12/02/2020] [Indexed: 12/21/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory disease that is initiated by the deposition and accumulation of low-density lipoproteins in the artery wall. In this review, we will discuss the role of T- and B-cells in human plaques at different stages of atherosclerosis and the utility of profiling circulating immune cells to monitor atherosclerosis progression. Evidence supports a proatherogenic role for intraplaque T helper type 1 (Th1) cells, CD4+CD28null T-cells, and natural killer T-cells, whereas Th2 cells and regulatory T-cells (Treg) have an atheroprotective role. Several studies indicate that intraplaque T-cells are activated upon recognition of endogenous antigens including heat shock protein 60 and oxidized low-density lipoprotein, but antigens derived from pathogens can also trigger T-cell proliferation and cytokine production. Future studies are needed to assess whether circulating cellular biomarkers can improve identification of vulnerable lesions so that effective intervention can be implemented before clinical manifestations are apparent.
Collapse
|
|
46
|
Alizadehsani R, Khosravi A, Roshanzamir M, Abdar M, Sarrafzadegan N, Shafie D, Khozeimeh F, Shoeibi A, Nahavandi S, Panahiazar M, Bishara A, Beygui RE, Puri R, Kapadia S, Tan RS, Acharya UR. Coronary artery disease detection using artificial intelligence techniques: A survey of trends, geographical differences and diagnostic features 1991-2020. Comput Biol Med 2020; 128:104095. [PMID: 33217660 DOI: 10.1016/j.compbiomed.2020.104095] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/24/2020] [Accepted: 10/24/2020] [Indexed: 02/06/2023]
Abstract
While coronary angiography is the gold standard diagnostic tool for coronary artery disease (CAD), but it is associated with procedural risk, it is an invasive technique requiring arterial puncture, and it subjects the patient to radiation and iodinated contrast exposure. Artificial intelligence (AI) can provide a pretest probability of disease that can be used to triage patients for angiography. This review comprehensively investigates published papers in the domain of CAD detection using different AI techniques from 1991 to 2020, in order to discern broad trends and geographical differences. Moreover, key decision factors affecting CAD diagnosis are identified for different parts of the world by aggregating the results from different studies. In this study, all datasets that have been used for the studies for CAD detection, their properties, and achieved performances using various AI techniques, are presented, compared, and analyzed. In particular, the effectiveness of machine learning (ML) and deep learning (DL) techniques to diagnose and predict CAD are reviewed. From PubMed, Scopus, Ovid MEDLINE, and Google Scholar search, 500 papers were selected to be investigated. Among these selected papers, 256 papers met our criteria and hence were included in this study. Our findings demonstrate that AI-based techniques have been increasingly applied for the detection of CAD since 2008. AI-based techniques that utilized electrocardiography (ECG), demographic characteristics, symptoms, physical examination findings, and heart rate signals, reported high accuracy for the detection of CAD. In these papers, the authors ranked the features based on their assessed clinical importance with ML techniques. The results demonstrate that the attribution of the relative importance of ML features for CAD diagnosis is different among countries. More recently, DL methods have yielded high CAD detection performance using ECG signals, which drives its burgeoning adoption.
Collapse
Affiliation(s)
- Roohallah Alizadehsani
- Institute for Intelligent Systems Research and Innovations (IISRI), Deakin University, Geelong, Australia
| | - Abbas Khosravi
- Institute for Intelligent Systems Research and Innovations (IISRI), Deakin University, Geelong, Australia
| | - Mohamad Roshanzamir
- Department of Engineering, Fasa Branch, Islamic Azad University, Post Box No 364, Fasa, Fars, 7461789818, Iran
| | - Moloud Abdar
- Institute for Intelligent Systems Research and Innovations (IISRI), Deakin University, Geelong, Australia
| | - Nizal Sarrafzadegan
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Khorram Ave, Isfahan, Iran; Faculty of Medicine, SPPH, University of British Columbia, Vancouver, BC, Canada.
| | - Davood Shafie
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fahime Khozeimeh
- Institute for Intelligent Systems Research and Innovations (IISRI), Deakin University, Geelong, Australia
| | - Afshin Shoeibi
- Computer Engineering Department, Ferdowsi University of Mashhad, Mashhad, Iran; Faculty of Electrical and Computer Engineering, Biomedical Data Acquisition Lab, K. N. Toosi University of Technology, Tehran, Iran
| | - Saeid Nahavandi
- Institute for Intelligent Systems Research and Innovations (IISRI), Deakin University, Geelong, Australia
| | - Maryam Panahiazar
- Institute for Computational Health Sciences, University of California, San Francisco, USA
| | - Andrew Bishara
- Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA
| | - Ramin E Beygui
- Cardiovascular Surgery Division, Department of Surgery, University of California, San Francisco, CA, USA
| | - Rishi Puri
- Department of Cardiovascular Medicine, Cleveland Clinic, OH, USA
| | - Samir Kapadia
- Department of Cardiovascular Medicine, Cleveland Clinic, OH, USA
| | - Ru-San Tan
- Department of Cardiology, National Heart Centre Singapore, Singapore
| | - U Rajendra Acharya
- Department of Electronics and Computer Engineering, Ngee Ann Polytechnic, Singapore; Department of Biomedical Engineering, School of Science and Technology, Singapore University of Social Sciences, Singapore; Department of Bioinformatics and Medical Engineering, Asia University, Taiwan
| |
Collapse
|
|
47
|
Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits. Clin Epigenetics 2020; 12:157. [PMID: 33092652 PMCID: PMC7579899 DOI: 10.1186/s13148-020-00951-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. RESULTS We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. CONCLUSIONS Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.
Collapse
|
|
48
|
Weighted gene co-expression network analysis identifies RHOH and TRAF1 as key candidate genes for psoriatic arthritis. Clin Rheumatol 2020; 40:1381-1391. [PMID: 32959187 DOI: 10.1007/s10067-020-05395-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/12/2020] [Accepted: 09/12/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Psoriatic arthritis (PsA) is inflammatory arthritis associated with psoriasis, which involves the axial joint and the distal interphalangeal joints. Its clinical features are varied, often resulting in delayed diagnosis and treatment. Improved knowledge about disease mechanisms will catalyze the rapid development of effective targeted therapies for this disease. The perturbations in the gene co-expression network may not be detected by the differential expression analysis of the microarray. This study aims to identify key modules and hub genes in psoriatic arthritis-applied WGCNA (weighted gene co-expression network analysis) on a microarray. METHODS This study downloaded the array data of GSE61281 from the gene expression overview (GEO) database, which includes 20 psoriatic arthritis samples and 12 healthy controls. The analysis was performed with the WGCNA package. Gene ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on these key modules. Candidate hub genes were identified using GS and MM measures, Cytoscape, and the online database STRING. RESULTS A total of 10 co-expression modules were constructed. The lightcyan module was identified as the key module. GO and KEGG pathway analyses were mainly enriched in dephosphorylation, regulation of small GTPase-mediated signal transduction, Ras signaling pathway, MAPK signaling pathway, and vascular smooth muscle contraction. Two hub genes, RHOH/TRAF1, were selected. CONCLUSIONS This finding may indicate that RHOH/TRAF1 play a critical role in the pathogenesis of PsA. This is one of the first studies in PsA using WGCNA, which may provide a new research direction for further understanding of the molecular mechanism and clinical application of PsA. Key points • The WGCNA method was applied to the expression profile microarray of psoriatic arthritis and the co-expression module was constructed. • Identify the key modules by combining the onset time of psoriasis in patients with psoriatic arthritis. • Three screening methods are used to identify and verify hub genes of key modules.
Collapse
|
|
49
|
Orekhov AN, Ivanova EA, Markin AM, Nikiforov NG, Sobenin IA. Genetics of Arterial-Wall-Specific Mechanisms in Atherosclerosis: Focus on Mitochondrial Mutations. Curr Atheroscler Rep 2020; 22:54. [PMID: 32772280 DOI: 10.1007/s11883-020-00873-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Mutations in both nuclear and mitochondrial genes are associated with the development of atherosclerotic lesions in arteries and may provide a partial explanation to the focal nature of lesion distribution in the arterial wall. This review is aimed to discuss the genetic aspects of atherogenesis with a special focus on possible pro-atherogenic variants (mutations) of the nuclear and mitochondrial genomes that may be implicated in atherosclerosis development and progression. RECENT FINDINGS Mutations in the nuclear genes generally do not cause a phenotype restricted to a specific vascular wall cell and manifest themselves mostly at the organism level. Such mutations can act as important contributors to changes in lipid metabolism and modulate other risk factors of atherosclerosis. By contrast, mitochondrial DNA (mtDNA) mutations occurring locally in the arterial wall cells or in circulating immune cells may play a site-specific role in atherogenesis. The mosaic distribution of heteroplasmic mtDNA mutations in the arterial wall tissue may explain, at least to some extent, the locality and focality of atherosclerotic lesions distribution. The genetic mechanisms of atherogenesis include alterations of both nuclear and mitochondrial genomes. Altered lipid metabolism and inflammatory response of resident arterial wall and circulating immune cells may be related to mtDNA damage and defective mitophagy, which hinders clearance of dysfunctional mitochondria. Mutations of mtDNA can have mosaic distribution and locally affect functionality of endothelial and subendothelial intimal cells in the arterial wall contributing to atherosclerotic lesion development.
Collapse
Affiliation(s)
- Alexander N Orekhov
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow, Russia, 125315. .,Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, Moscow, Russia, 117418.
| | - Ekaterina A Ivanova
- Institute for Atherosclerosis Research, 2-1-207 Osennyaya Street, Moscow, Russia, 121609.
| | - Alexander M Markin
- Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, Moscow, Russia, 117418
| | - Nikita G Nikiforov
- Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences, 34/5 Vavilova Street, Moscow, Russia, 119334.,Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, Moscow, Russia, 121552
| | - Igor A Sobenin
- Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow, Russia, 125315.,Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 15A 3-rd Cherepkovskaya Street, Moscow, Russia, 121552
| |
Collapse
|
|
50
|
Shikatani EA, Besla R, Ensan S, Upadhye A, Khyzha N, Li A, Emoto T, Chiu F, Degousee N, Moreau JM, Perry HM, Thayaparan D, Cheng HS, Pacheco S, Smyth D, Noyan H, Zavitz CCJ, Bauer CMT, Hilgendorf I, Libby P, Swirski FK, Gommerman JL, Fish JE, Stampfli MR, Cybulsky MI, Rubin BB, Paige CJ, Bender TP, McNamara CA, Husain M, Robbins CS. c-Myb Exacerbates Atherosclerosis through Regulation of Protective IgM-Producing Antibody-Secreting Cells. Cell Rep 2020; 27:2304-2312.e6. [PMID: 31116977 DOI: 10.1016/j.celrep.2019.04.090] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 03/09/2019] [Accepted: 04/17/2019] [Indexed: 11/17/2022] Open
Abstract
Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease.
Collapse
Affiliation(s)
- Eric A Shikatani
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada
| | - Rickvinder Besla
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada.
| | - Sherine Ensan
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
| | - Aditi Upadhye
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA
| | - Nadiya Khyzha
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Angela Li
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
| | - Takuo Emoto
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Felix Chiu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada
| | - Norbert Degousee
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Joshua M Moreau
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada
| | - Heather M Perry
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA
| | - Danya Thayaparan
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S148, Canada
| | - Henry S Cheng
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada
| | - Shaun Pacheco
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - David Smyth
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Hossein Noyan
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Caleb C J Zavitz
- Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Carla M T Bauer
- Hoffmann-La Roche, pRED, Pharma Research & Early Development, DTA Inflammation, Nutley, NJ 07110, USA
| | - Ingo Hilgendorf
- Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany
| | - Peter Libby
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Filip K Swirski
- Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | | | - Jason E Fish
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada
| | - Martin R Stampfli
- McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S148, Canada
| | - Myron I Cybulsky
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada
| | - Barry B Rubin
- Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada
| | - Christopher J Paige
- Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2M9, Canada
| | - Timothy P Bender
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA; Beirne B. Carter Center for Immunology Research, University of Virginia Health System, Charlottesville, VA 22903, USA
| | - Coleen A McNamara
- Division of Cardiology, Robert Berne Cardiovascular Center, University of Virginia, Charlottesville, VA 22908, USA
| | - Mansoor Husain
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G2M9, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada; McEwen Centre for Regenerative Medicine, Toronto, ON, Canada
| | - Clinton S Robbins
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S1A1, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S1A1, Canada; Toronto General Research Institute, University Health Network, Toronto, ON M5G1L7, Canada; Peter Munk Cardiac Centre, Toronto, ON M5G1L7, Canada.
| |
Collapse
|