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Guan C, Chen R, Wang Y. Inflammatory markers mediate association of AIP with kidney failure risk: data from National Health and Nutrition Examination Survey (NHANES) 2005-2018. Ren Fail 2025; 47:2486565. [PMID: 40230193 PMCID: PMC12001854 DOI: 10.1080/0886022x.2025.2486565] [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: 07/25/2024] [Revised: 03/21/2025] [Accepted: 03/22/2025] [Indexed: 04/16/2025] Open
Abstract
Dyslipidemia and inflammation often coexist in the progression of kidney failure, with the atherosclerosis index of plasma (AIP) serving as a valuable marker for monitoring dyslipidemia. This cross-sectional study analyzed data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005 to 2018, involving a total of 10,358 participants. AIP was calculated as the logarithmic ratio (base 10) of triglycerides to high-density lipoprotein cholesterol (log10[TG/HDL-C]), while kidney failure was assessed through self-reported physician diagnosis. Logistic regression models and restricted cubic splines (RCS) were utilized to examine the association between AIP and the risk of kidney failure, with additional subgroup analyses performed to explore potential interactions. Mediation analyses were conducted to investigate whether inflammatory markers mediated the relationship between AIP and kidney failure. In logistic regression, after adjusting for all covariates, AIP was found to be positively associated with the risk of kidney failure [OR = 1.74 (95% CI: 1.04-2.92)], and a linear relationship between AIP and kidney failure risk was observed (P-non-linear = 0.4050). Mediation analysis revealed that segmented neutrophils, eosinophils, and monocytes partially mediated the association between AIP and kidney failure, with mediation proportions of 19.65%, 2.44%, and 7.25%, respectively. These findings suggest that Higher AIP was associated with an increased risk of kidney failure, with segmented neutrophils, eosinophils, and monocytes serving as partial mediators. The results provide valuable insights into the role of inflammation in kidney failure and highlight potential avenues for its prevention.
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Affiliation(s)
- Chengjing Guan
- Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ruixue Chen
- Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yu Wang
- Department of Nephrology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
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2
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Wiyono AV, Ardinal AP, Raharjo PP. Unraveling the significance of innate inflammation in vascular disease. Int Rev Immunol 2025:1-16. [PMID: 40255209 DOI: 10.1080/08830185.2025.2489346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 02/06/2025] [Accepted: 03/31/2025] [Indexed: 04/22/2025]
Abstract
Atheroma formation is initiated by the activation of endothelial and smooth muscle cells, as well as immune cells, including neutrophils, lymphocytes, monocytes, macrophages, and dendritic cells. Monocytes, macrophages, and neutrophils are the innate immune cells that provide a rapid initial line of defence against vascular disease. These cells have a short lifespan and cannot retain memories, making them potential therapeutic targets for the inflammatory process associated with atherosclerosis. In addition, macrophages comprise the majority of vessel wall infiltrates and are, therefore, implicated in all stages of atherosclerosis progression. Neutrophils are the most common type of leukocyte found in circulation, and their high levels of matrix-degrading protease explain their significance in fibrous cap destabilization. However, the activation of immune cells becomes more complex by various microenvironmental stimuli and cytokines, which ultimately transform immune cells into their pro-inflammatory state. Different types of macrophage subsets with distinct functions in inflammation, such as M1 macrophages, cause an increase in pro-inflammatory cytokines and produce reactive oxygen species and nitric oxide, further worsening the disease. This review aims to shed light on immune-mediated inflammation in cardiovascular disease by focusing on the role of macrophage subsets in vascular inflammation and plaque stability, as well as the interaction between neutrophils and monocyte-macrophages.
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Affiliation(s)
- Alice Valeria Wiyono
- Faculty of Life Sciences & Medicine, King's College London, London, UK
- Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Padjadjaran, Rumah Sakit Umum Pusat Hasan Sadikin, Bandung, Indonesia
| | | | - Pradana Pratomo Raharjo
- Department of Cardiology and Vascular Medicine, Faculty of Medicine Universitas Padjadjaran, Rumah Sakit Umum Pusat Hasan Sadikin, Bandung, Indonesia
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Kanuri B, Maremanda KP, Chattopadhyay D, Essop MF, Lee MKS, Murphy AJ, Nagareddy PR. Redefining Macrophage Heterogeneity in Atherosclerosis: A Focus on Possible Therapeutic Implications. Compr Physiol 2025; 15:e70008. [PMID: 40108774 DOI: 10.1002/cph4.70008] [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: 12/28/2024] [Revised: 02/20/2025] [Accepted: 03/08/2025] [Indexed: 03/22/2025]
Abstract
Atherosclerosis is a lipid disorder where modified lipids (especially oxidized LDL) induce macrophage foam cell formation in the aorta. Its pathogenesis involves a continuum of persistent inflammation accompanied by dysregulated anti-inflammatory responses. Changes in the immune cell status due to differences in the lesional microenvironment are crucial in terms of plaque development, its progression, and plaque rupture. Ly6Chi monocytes generated through both medullary and extramedullary cascades act as one of the major sources of plaque macrophages and thereby foam cells. Both monocytes and monocyte-derived macrophages also participate in pathological events in atherosclerosis-associated multiple organ systems through inter-organ communications. For years, macrophage phenotypes M1 and M2 have been shown to perpetuate inflammatory and resolution responses; nevertheless, such a dualistic classification is too simplistic and contains severe drawbacks. As the lesion microenvironment is enriched with multiple mediators that possess the ability to activate macrophages to diverse phenotypes, it is obvious that such cells should demonstrate substantial heterogeneity. Considerable research in this regard has indicated the presence of additional macrophage phenotypes that are exclusive to atherosclerotic plaques, namely Mox, M4, Mhem, and M(Hb) type. Furthermore, although the concept of macrophage clusters has come to the fore in recent years with the evolution of high-dimensional techniques, classifications based on such 'OMICS' approaches require extensive functional validation as well as metabolic phenotyping. Bearing this in mind, the current review provides an overview of the status of different macrophage populations and their role during atherosclerosis and also outlines possible therapeutic implications.
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Affiliation(s)
- Babunageswararao Kanuri
- Department of Internal Medicine, Section of Cardiovascular Diseases, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
| | - Krishna P Maremanda
- Department of Internal Medicine, Section of Cardiovascular Diseases, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
| | - Dipanjan Chattopadhyay
- Department of Internal Medicine, Section of Cardiovascular Diseases, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
| | - M Faadiel Essop
- Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Man Kit Sam Lee
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Andrew J Murphy
- Division of Immunometabolism, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Prabhakara R Nagareddy
- Department of Internal Medicine, Section of Cardiovascular Diseases, University of Oklahoma Health Sciences Center (OUHSC), Oklahoma City, Oklahoma, USA
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Lai T, Liang Y, Guan F, Chen Y, Hu K. Association between remnant cholesterol and arterial stiffness: Evidence from NHANES 1999-2018. Nutr Metab Cardiovasc Dis 2025:104013. [PMID: 40199709 DOI: 10.1016/j.numecd.2025.104013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 02/13/2025] [Accepted: 03/10/2025] [Indexed: 04/10/2025]
Abstract
BACKGROUND AND AIM Remnant cholesterol (RC), an emerging cardiovascular risk factor, has garnered increasing attention in atherosclerotic cardiovascular disease (ASCVD) research, though its relationship with arterial stiffness remains incompletely understood. This study investigated the association between RC and estimated pulse wave velocity (ePWV), a reliable marker of arterial stiffness, with the goal of enhancing our understanding of RC's role in cardiovascular risk assessment. METHODS AND RESULTS This study utilized the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018, including 12,505 participants aged 20 years and above. Weighted linear regression, restricted cubic splines (RCS), and subgroup analyses were used to explore the association between RC levels and ePWV. Analysis revealed a significant positive association between RC levels and ePWV, with participants in the highest RC quintile (Q5) exhibiting substantially elevated ePWV compared to those in the lowest quintile (Q1). Notably, RCS analysis demonstrated a non-linear relationship characterized by a saturation effect (p-nonlinear <0.05). Subgroup analyses indicated stronger associations among specific demographic groups, including individuals under 40 years, females, non-Hispanic whites, and those above the poverty level (all interaction p < 0.05). Furthermore, mediation analysis found that various inflammatory markers such as neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR) played a mediating role in this association. CONCLUSION Increased arterial stiffness is associated with higher RC levels, demonstrating a saturation effect at elevated concentrations. This association is partially mediated by NLR, MLR, and NEU, and was stronger among younger, females, non-Hispanic whites, and non-impoverished individuals.
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Affiliation(s)
- Tianjie Lai
- Department of Spine Surgery, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong, 512000, China.
| | - Yiyin Liang
- Department of Otorhinolaryngology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830000, China.
| | - Fenglei Guan
- Department of Cardiology, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong, 512000, China.
| | - Yunxian Chen
- Department of Cardiology, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong, 512000, China.
| | - Konghe Hu
- Department of Spine Surgery, The Affiliated Yuebei People's Hospital of Shantou University Medical College, Shaoguan, Guangdong, 512000, China.
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Wang J, Zhong MY, Liu YX, Yu JY, Wang YB, Zhang XJ, Sun HP. Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway. Acta Pharmacol Sin 2025; 46:662-671. [PMID: 39567750 PMCID: PMC11845675 DOI: 10.1038/s41401-024-01417-2] [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: 06/17/2024] [Accepted: 10/22/2024] [Indexed: 11/22/2024]
Abstract
Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800 nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.
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Affiliation(s)
- Ji Wang
- Department of Clinical Laboratory, The Second People's Hospital of Hefei / Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, China
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Meng-Yu Zhong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yun-Xia Liu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- The Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Jia-Yu Yu
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Yi-Bin Wang
- The Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Singapore
| | - Xue-Jiao Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
| | - Hai-Peng Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
- Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
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Ajoolabady A, Pratico D, Lin L, Mantzoros CS, Bahijri S, Tuomilehto J, Ren J. Inflammation in atherosclerosis: pathophysiology and mechanisms. Cell Death Dis 2024; 15:817. [PMID: 39528464 PMCID: PMC11555284 DOI: 10.1038/s41419-024-07166-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/26/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024]
Abstract
Atherosclerosis imposes a heavy burden on cardiovascular health due to its indispensable role in the pathogenesis of cardiovascular disease (CVD) such as coronary artery disease and heart failure. Ample clinical and experimental evidence has corroborated the vital role of inflammation in the pathophysiology of atherosclerosis. Hence, the demand for preclinical research into atherosclerotic inflammation is on the horizon. Indeed, the acquisition of an in-depth knowledge of the molecular and cellular mechanisms of inflammation in atherosclerosis should allow us to identify novel therapeutic targets with translational merits. In this review, we aimed to critically discuss and speculate on the recently identified molecular and cellular mechanisms of inflammation in atherosclerosis. Moreover, we delineated various signaling cascades and proinflammatory responses in macrophages and other leukocytes that promote plaque inflammation and atherosclerosis. In the end, we highlighted potential therapeutic targets, the pros and cons of current interventions, as well as anti-inflammatory and atheroprotective mechanisms.
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Affiliation(s)
- Amir Ajoolabady
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Domenico Pratico
- Alzheimer's Center at Temple, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Ling Lin
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | | | - Suhad Bahijri
- Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
| | - Jaakko Tuomilehto
- Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia.
- Department of Public Health, University of Helsinki, Helsinki, Finland.
- Health Promotion Unit, Finnish Institute for Health and Welfare, Helsinki, Finland.
| | - Jun Ren
- Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
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He Y, Liu Y, Li R, Xiang A, Chen X, Yu Q, Su P. The role of autophagy/lipophagy in the response of osteoblastic cells to hyperlipidemia (Review). Exp Ther Med 2024; 28:328. [PMID: 38979020 PMCID: PMC11229398 DOI: 10.3892/etm.2024.12617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/10/2024] [Indexed: 07/10/2024] Open
Abstract
There has been interest in the connection between cardiovascular diseases and osteoporosis, both of which share hyperlipidemia as a common pathological basis. Osteoporosis is a progressive metabolic bone disease characterized by reduced bone mass, deteriorated bone microstructure, increased bone fragility and heightened risk of bone fractures. Dysfunction of osteoblastic cells, vital for bone formation, is induced by excessive internalization of lipids under hyperlipidemic conditions, forming the crux of hyperlipidemia-associated osteoporosis. Autophagy, a process fundamental to cell self-regulation, serves a critical role in osteoblastic cell function and bone formation. When activated by lipids, lipophagy inhibits osteoblastic cell differentiation in response to elevated lipid concentrations, resulting in reduced bone mass and osteoporosis. However, an in-depth understanding of the precise roles and mechanisms of lipophagy in the regulation of osteoblastic cell function is required. Study of the molecular mechanisms governing osteoblastic cell response to excessive lipids can result in a clearer understanding of osteoporosis; therefore, potential strategies for preventing hyperlipidemia-induced osteoporosis can be developed. The present review discusses recent progress in elucidating the molecular mechanisms of lipophagy in the regulation of osteoblastic cell function, offering insights into hyperlipidemia-induced osteoporosis.
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Affiliation(s)
- Yizhang He
- Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Yantong Liu
- School of Basic Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Ran Li
- Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Aoqi Xiang
- Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Xiaochang Chen
- Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Qi Yu
- Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
| | - Peihong Su
- Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, Shaanxi 710021, P.R. China
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Chang FY, Huang CH, Yang CH, Chang JT, Yang CM, Ho TC, Hsieh YT, Lai TT, Lin CW, Lin CP, Chen YC, Lai YJ, Chen PL, Hsu JS, Chen TC. Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study. Clin Exp Ophthalmol 2024; 52:655-664. [PMID: 38757252 DOI: 10.1111/ceo.14388] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 04/24/2024] [Accepted: 05/04/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. METHODS This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. RESULTS In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). CONCLUSIONS Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.
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Affiliation(s)
- Fang-Yu Chang
- College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chu-Hsuan Huang
- Department of Ophthalmology, Cathay General Hospital, Taipei, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chang-Hao Yang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jung-Tzu Chang
- Department of Ophthalmology, Cathay General Hospital, Taipei, Taiwan
| | - Chung-May Yang
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tzzy-Chang Ho
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ting Hsieh
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tso-Ting Lai
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chao-Wen Lin
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chang-Pin Lin
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Chieh Chen
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ying-Ju Lai
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Pei-Lung Chen
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Jacob Shujui Hsu
- Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ta-Ching Chen
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Ophthalmology, College of Medicine, National Taiwan University, Taipei, Taiwan
- Center of Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan
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9
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Kleimann P, Irschfeld LM, Grandoch M, Flögel U, Temme S. Trained Innate Immunity in Animal Models of Cardiovascular Diseases. Int J Mol Sci 2024; 25:2312. [PMID: 38396989 PMCID: PMC10889825 DOI: 10.3390/ijms25042312] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/11/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Acquisition of immunological memory is an important evolutionary strategy that evolved to protect the host from repetitive challenges from infectious agents. It was believed for a long time that memory formation exclusively occurs in the adaptive part of the immune system with the formation of highly specific memory T cells and B cells. In the past 10-15 years, it has become clear that innate immune cells, such as monocytes, natural killer cells, or neutrophil granulocytes, also have the ability to generate some kind of memory. After the exposure of innate immune cells to certain stimuli, these cells develop an enhanced secondary response with increased cytokine secretion even after an encounter with an unrelated stimulus. This phenomenon has been termed trained innate immunity (TI) and is associated with epigenetic modifications (histone methylation, acetylation) and metabolic alterations (elevated glycolysis, lactate production). TI has been observed in tissue-resident or circulating immune cells but also in bone marrow progenitors. Risk-factors for cardiovascular diseases (CVDs) which are associated with low-grade inflammation, such as hyperglycemia, obesity, or high salt, can also induce TI with a profound impact on the development and progression of CVDs. In this review, we briefly describe basic mechanisms of TI and summarize animal studies which specifically focus on TI in the context of CVDs.
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Affiliation(s)
- Patricia Kleimann
- Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (P.K.); (U.F.)
| | - Lisa-Marie Irschfeld
- Department of Radiation Oncology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
| | - Maria Grandoch
- Institute of Translational Pharmacology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany;
- Cardiovascular Research Institute Düsseldorf (CARID), University Hospital, 40225 Düsseldorf, Germany
| | - Ulrich Flögel
- Institute of Molecular Cardiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany; (P.K.); (U.F.)
- Cardiovascular Research Institute Düsseldorf (CARID), University Hospital, 40225 Düsseldorf, Germany
| | - Sebastian Temme
- Cardiovascular Research Institute Düsseldorf (CARID), University Hospital, 40225 Düsseldorf, Germany
- Department of Anesthesiology, Faculty of Medicine, University Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany
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10
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Lu C, Donners MMPC, de Baaij JBJ, Jin H, Otten JJT, Manca M, van Zonneveld AJ, Jukema JW, Kraaijeveld A, Kuiper J, Pasterkamp G, Mees B, Sluimer JC, Cavill R, Karel JMH, Goossens P, Biessen EAL. Identification of a gene network driving the attenuated response to lipopolysaccharide of monocytes from hypertensive coronary artery disease patients. Front Immunol 2024; 15:1286382. [PMID: 38410507 PMCID: PMC10894924 DOI: 10.3389/fimmu.2024.1286382] [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: 08/31/2023] [Accepted: 01/24/2024] [Indexed: 02/28/2024] Open
Abstract
Introduction The impact of cardiovascular disease (CVD) risk factors, encompassing various biological determinants and unhealthy lifestyles, on the functional dynamics of circulating monocytes-a pivotal cell type in CVD pathophysiology remains elusive. In this study, we aimed to elucidate the influence of CVD risk factors on monocyte transcriptional responses to an infectious stimulus. Methods We conducted a comparative analysis of monocyte gene expression profiles from the CTMM - CIRCULATING CELLS Cohort of coronary artery disease (CAD) patients, at baseline and after lipopolysaccharide (LPS) stimulation. Gene co-expression analysis was used to identify gene modules and their correlations with CVD risk factors, while pivotal transcription factors controlling the hub genes in these modules were identified by regulatory network analyses. The identified gene module was subjected to a drug repurposing screen, utilizing the LINCS L1000 database. Results Monocyte responsiveness to LPS showed a highly significant, negative correlation with blood pressure levels (ρ< -0.4; P<10-80). We identified a ZNF12/ZBTB43-driven gene module closely linked to diastolic blood pressure, suggesting that monocyte responses to infectious stimuli, such as LPS, are attenuated in CAD patients with elevated diastolic blood pressure. This attenuation appears associated with a dampening of the LPS-induced suppression of oxidative phosphorylation. Finally, we identified the serine-threonine inhibitor MW-STK33-97 as a drug candidate capable of reversing this aberrant LPS response. Conclusions Monocyte responses to infectious stimuli may be hampered in CAD patients with high diastolic blood pressure and this attenuated inflammatory response may be reversed by the serine-threonine inhibitor MW-STK33-97. Whether the identified gene module is a mere indicator of, or causal factor in diastolic blood pressure and the associated dampened LPS responses remains to be determined.
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Affiliation(s)
- Chang Lu
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
- Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany
| | - Marjo M P C Donners
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
| | - Julius B J de Baaij
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
| | - Han Jin
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jeroen J T Otten
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
| | | | - Anton Jan van Zonneveld
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, Netherlands
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands
- Netherlands Heart Institute, Utrecht, Netherlands
| | - Adriaan Kraaijeveld
- Department of Cardiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Johan Kuiper
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Gerard Pasterkamp
- Circulatory Health Research Center, University Medical Center Utrecht, Utrecht, Netherlands
| | - Barend Mees
- Department of Vascular Surgery, Maastricht University Medical Center, Maastricht, Netherlands
| | - Judith C Sluimer
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
- Centre for Cardiovascular Science (CVS), University of Edinburgh, Edinburgh, United Kingdom
| | - Rachel Cavill
- Department of Advanced Computing Sciences, Maastricht University, Maastricht, Netherlands
| | - Joël M H Karel
- Department of Advanced Computing Sciences, Maastricht University, Maastricht, Netherlands
| | - Pieter Goossens
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
| | - Erik A L Biessen
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, Netherlands
- Institute for Molecular Cardiovascular Research, Klinikum RWTH Aachen, Aachen, Germany
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11
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Christ A, Maas SL, Jin H, Lu C, Legein B, Wijnands E, Temmerman L, Otten J, Isaacs A, Zenke M, Stoll M, Biessen EAL, van der Vorst EPC. In situ lipid-loading activates peripheral dendritic cell subsets characterized by cellular ROS accumulation but compromises their capacity to prime naïve T cells. Free Radic Biol Med 2024; 210:406-415. [PMID: 38061606 DOI: 10.1016/j.freeradbiomed.2023.11.044] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 11/30/2023] [Indexed: 12/22/2023]
Abstract
BACKGROUND AND AIMS Dendritic cells (DCs), professional antigen-presenting cells, play an important role in pathologies by controlling adaptive immune responses. However, their adaptation to and functionality in hypercholesterolemia, a driving factor in disease onset and progression of atherosclerosis remains to be established. METHODS In this study, we addressed the immediate impact of high fat diet-induced hypercholesterolemia in low-density lipoprotein receptor deficient (Ldlr-/-) mice on separate DC subsets, their compartmentalization and functionality. RESULTS While hypercholesterolemia induced a significant rise in bone marrow myeloid and dendritic cell progenitor (MDP) frequency and proliferation rate after high fat diet feeding, it did not affect DC subset numbers in lymphoid tissue. Hypercholesterolemia led to almost immediate and persistent augmentation in granularity of conventional DCs (cDCs), in particular cDC2, reflecting progressive lipid accumulation by these subsets. Plasmacytoid DCs were only marginally and transiently affected. Lipid loading increased co-stimulatory molecule expression and ROS accumulation by cDC2. Despite this hyperactivation, lipid-laden cDC2 displayed a profoundly reduced capacity to stimulate naïve CD4+ T cells. CONCLUSION Our data provide evidence that in hypercholesterolemic conditions, peripheral cDC2 subsets engulf lipids in situ, leading to a more activated status characterized by cellular ROS accumulation while, paradoxically, compromising their T cell priming ability. These findings will have repercussions not only for lipid driven cardiometabolic disorders like atherosclerosis, but also for adaptive immune responses to pathogens and/or endogenous (neo) antigens under conditions of hyperlipidemia.
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Affiliation(s)
- Anette Christ
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Health Office Frankfurt/Main, Frankfurt/Main, Germany.
| | - Sanne L Maas
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
| | - Han Jin
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Chang Lu
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Bart Legein
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Erwin Wijnands
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Lieve Temmerman
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Jeroen Otten
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands
| | - Aaron Isaacs
- Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands
| | - Martin Zenke
- Institute for Biomedical Engineering, Department of Cell Biology, RWTH Aachen University Medical School, Aachen, Germany; Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, 52074, Aachen, Germany; Department of Hematology, Oncology and Stem Cell Transplantation, RWTH Aachen University Medical School, 52074, Aachen, Germany
| | - Monika Stoll
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Genetic Epidemiology, Institute for Human Genetics, Westfälische Wilhelms-University, Münster, Germany
| | - Erik A L Biessen
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
| | - Emiel P C van der Vorst
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, Netherlands; Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany.
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12
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Wang H, Pang J, Zhang S, Yu Q, Chen Y, Wang L, Sheng M, Dan J, Tang W. Single-cell and bulk RNA-sequencing analysis to predict the role and clinical value of CD36 in lung squamous cell carcinoma. Heliyon 2023; 9:e22201. [PMID: 38034730 PMCID: PMC10682125 DOI: 10.1016/j.heliyon.2023.e22201] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 10/21/2023] [Accepted: 11/06/2023] [Indexed: 12/02/2023] Open
Abstract
The majority of patients with lung squamous cell carcinoma are diagnosed at an advanced stage, which poses a challenge to the efficacy of chemotherapy. Therefore, the search for an early biomarker needs to be addressed. CD36 is a scavenger receptor expressed in various cell types. It has been reported that it is closely related to the occurrence and development of many kinds of tumours. However, its role in lung squamous cell carcinoma has not been reported. Our research aims to reveal the role of CD36 in lung squamous cell carcinoma by integrating single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data. We used bioinformatics methods to explore the potential carcinogenicity of CD36 by analysing the data from the cancer genome map (TCGA), gene expression comprehensive map (GEO), human protein map (HPA) comparative toxicology genomics database (CTD) and other resources. Our study dissected the relationship between CD36 and prognosis and gene correlation, functional analysis, mutation of different tumours, infiltration of immune cells and exploring the interaction between CD36 and chemicals. The results showed that the expression of CD36 was heterogeneous. Compared with normal patients, the expression was low in lung squamous cell carcinoma. In addition, CD36 showed early diagnostic value in four kinds of tumours (LUSC, BLCA, BRCA and KIRC) and was positively or negatively correlated with the prognosis of different tumours. The relationship between CD36 and the tumour immune microenvironment was revealed by immunoinfiltration analysis, and many drugs that might target CD36 were identified by the comparative toxicological genomics database (CTD). In summary, through pancancer analysis, we found and verified for the first time that CD36 may play a role in the detection of lung squamous cell carcinoma. In addition, it has high specificity and sensitivity in detecting cancer. Therefore, CD36 can be used as an auxiliary index for early tumour diagnosis and a prognostic marker for lung squamous cell carcinoma.
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Affiliation(s)
- Hui Wang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Jianyu Pang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Shuojie Zhang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Qian Yu
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Yongzhi Chen
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Lulin Wang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Miaomiao Sheng
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Juhua Dan
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
| | - Wenru Tang
- Laboratory of Molecular Genetics of Aging & Tumor, Medicine School, Kunming University of Science and Technology, No. 727, Jingming South Road, Kunming City, Yunnan Province, China
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Mlera L, Collins-McMillen D, Zeltzer S, Buehler JC, Moy M, Zarrella K, Caviness K, Cicchini L, Tafoya DJ, Goodrum F. Liver X Receptor-Inducible Host E3 Ligase IDOL Targets a Human Cytomegalovirus Reactivation Determinant. J Virol 2023; 97:e0075823. [PMID: 37338407 PMCID: PMC10373547 DOI: 10.1128/jvi.00758-23] [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: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 06/21/2023] Open
Abstract
Liver X receptor (LXR) signaling broadly restricts virus replication; however, the mechanisms of restriction are poorly defined. Here, we demonstrate that the cellular E3 ligase LXR-inducible degrader of low-density lipoprotein receptor (IDOL) targets the human cytomegalovirus (HMCV) UL136p33 protein for turnover. UL136 encodes multiple proteins that differentially impact latency and reactivation. UL136p33 is a determinant of reactivation. UL136p33 is targeted for rapid turnover by the proteasome, and its stabilization by mutation of lysine residues to arginine results in a failure to quiet replication for latency. We show that IDOL targets UL136p33 for turnover but not the stabilized variant. IDOL is highly expressed in undifferentiated hematopoietic cells where HCMV establishes latency but is sharply downregulated upon differentiation, a stimulus for reactivation. We hypothesize that IDOL maintains low levels of UL136p33 for the establishment of latency. Consistent with this hypothesis, knockdown of IDOL impacts viral gene expression in wild-type (WT) HCMV infection but not in infection where UL136p33 has been stabilized. Furthermore, the induction of LXR signaling restricts WT HCMV reactivation from latency but does not affect the replication of a recombinant virus expressing a stabilized variant of UL136p33. This work establishes the UL136p33-IDOL interaction as a key regulator of the bistable switch between latency and reactivation. It further suggests a model whereby a key viral determinant of HCMV reactivation is regulated by a host E3 ligase and acts as a sensor at the tipping point between the decision to maintain the latent state or exit latency for reactivation. IMPORTANCE Herpesviruses establish lifelong latent infections, which pose an important risk for disease particularly in the immunocompromised. Our work is focused on the betaherpesvirus human cytomegalovirus (HCMV) that latently infects the majority of the population worldwide. Defining the mechanisms by which HCMV establishes latency or reactivates from latency is important for controlling viral disease. Here, we demonstrate that the cellular inducible degrader of low-density lipoprotein receptor (IDOL) targets a HCMV determinant of reactivation for degradation. The instability of this determinant is important for the establishment of latency. This work defines a pivotal virus-host interaction that allows HCMV to sense changes in host biology to navigate decisions to establish latency or to replicate.
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Affiliation(s)
- Luwanika Mlera
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Donna Collins-McMillen
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Sebastian Zeltzer
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Jason C. Buehler
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Melissa Moy
- Graduate Interdisciplinary Program in Cancer Biology, University of Arizona, Tucson, Arizona, USA
| | - Kristen Zarrella
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
| | - Katie Caviness
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
- Graduate Interdisciplinary Program in Genetics, University of Arizona, Tucson, Arizona, USA
| | - Louis Cicchini
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA
| | - David J. Tafoya
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
| | - Felicia Goodrum
- Department of Immunobiology, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, University of Arizona, Tucson, Arizona, USA
- Graduate Interdisciplinary Program in Cancer Biology, University of Arizona, Tucson, Arizona, USA
- Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, USA
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Keeter WC, Moriarty AK, Akers R, Ma S, Mussbacher M, Nadler JL, Galkina EV. Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas of Ldlr-/- mice. Front Cardiovasc Med 2023; 10:1175673. [PMID: 37396582 PMCID: PMC10313069 DOI: 10.3389/fcvm.2023.1175673] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 05/19/2023] [Indexed: 07/04/2023] Open
Abstract
Background and aims Neutrophils drive atheroprogression and directly contribute to plaque instability. We recently identified signal transducer and activator of transcription 4 (STAT4) as a critical component for bacterial host defense in neutrophils. The STAT4-dependent functions of neutrophils in atherogenesis are unknown. Therefore, we investigated a contributory role of STAT4 in neutrophils during advanced atherosclerosis. Methods We generated myeloid-specific Stat4ΔLysMLdlr-/-, neutrophil-specific Stat4ΔS100A8Ldlr-/-, and control Stat4fl/flLdlr-/- mice. All groups were fed a high-fat/cholesterol diet (HFD-C) for 28 weeks to establish advanced atherosclerosis. Aortic root plaque burden and stability were assessed histologically by Movat pentachrome staining. Nanostring gene expression analysis was performed on isolated blood neutrophils. Flow cytometry was utilized to analyze hematopoiesis and blood neutrophil activation. In vivo homing of neutrophils to atherosclerotic plaques was performed by adoptively transferring prelabeled Stat4ΔLysMLdlr-/- and Stat4fl/flLdlr-/- bone marrow cells into aged atherosclerotic Apoe-/- mice and detected by flow cytometry. Results STAT4 deficiency in both myeloid-specific and neutrophil-specific mice provided similar reductions in aortic root plaque burden and improvements in plaque stability via reduction in necrotic core size, improved fibrous cap area, and increased vascular smooth muscle cell content within the fibrous cap. Myeloid-specific STAT4 deficiency resulted in decreased circulating neutrophils via reduced production of granulocyte-monocyte progenitors in the bone marrow. Neutrophil activation was dampened in HFD-C fed Stat4ΔLysMLdlr-/- mice via reduced mitochondrial superoxide production, attenuated surface expression of degranulation marker CD63, and reduced frequency of neutrophil-platelet aggregates. Myeloid-specific STAT4 deficiency diminished expression of chemokine receptors CCR1 and CCR2 and impaired in vivo neutrophil trafficking to atherosclerotic aorta. Conclusions Our work indicates a pro-atherogenic role for STAT4-dependent neutrophil activation and how it contributes to multiple factors of plaque instability during advanced atherosclerosis in mice.
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Affiliation(s)
- W. Coles Keeter
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Alina K. Moriarty
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
- Center for Integrative Neuroscience and Inflammatory Diseases, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Rachel Akers
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
- Rush Medical College, Rush University, Chicago, IL, United States
| | - Shelby Ma
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
| | - Marion Mussbacher
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
- Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, University of Graz, Graz, Austria
| | - Jerry L. Nadler
- Department of Medicine and Pharmacology, New York Medical College, Valhalla, NY, United States
| | - Elena V. Galkina
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, United States
- Center for Integrative Neuroscience and Inflammatory Diseases, Eastern Virginia Medical School, Norfolk, VA, United States
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Wakabayashi I, Daimon T. Hematometabolic Index as a New Discriminator of Cardiometabolic Risk in Middle-Aged Men with Polycythemia and High Leukocyte Count in Peripheral Blood. Metab Syndr Relat Disord 2023. [PMID: 37196206 DOI: 10.1089/met.2023.0011] [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: 05/19/2023] Open
Abstract
Background: Both polycythemia and high leukocyte count are associated with the risk of cardiovascular disease. However, it remains to be determined whether polycythemia and high leukocyte count show synergistic increasing effects on cardiometabolic risk. Methods: Cardiometabolic risk was evaluated by cardiometabolic index (CMI) and metabolic syndrome in a cohort of middle-aged men (n = 11,140) who underwent annual health check-up examinations. The subjects were divided into three tertile groups by hemoglobin concentration or leukocyte count in peripheral blood, and their relations with CMI and metabolic syndrome were investigated. A new index, named hematometabolic index (HMI), was defined as the product of hemoglobin concentration (g/dL)-minus-13.0 and leukocyte count (/μL)-minus-3000. Results: When the subjects were further classified by tertiles for hemoglobin concentration and leukocyte count into nine groups, the odds ratios for high CMI and metabolic syndrome of the group categorized in the highest (third) tertiles for both hemoglobin concentration and leukocyte count versus the group of the lowest (first) tertiles for both of them were highest among the nine groups. In receiver-operating characteristic (ROC) analysis for relationships of HMI with high CMI and metabolic syndrome, areas under the ROC curves (AUCs) were significantly larger than the reference level and tended to be smaller with an increase in age. In subjects from 30 to 39 years of age, the AUC for the relationship between HMI and metabolic syndrome was 0.707 (0.663-0.751) and the cutoff of HMI was 9850. Conclusions: HMI, reflecting hemoglobin concentration and leukocyte count, is thought to be a possible marker for discriminating cardiometabolic risk.
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Affiliation(s)
- Ichiro Wakabayashi
- Department of Environmental and Preventive Medicine and School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Takashi Daimon
- Department of Biostatistics, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
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Isorhynchophylline inhibits inflammatory responses in endothelial cells and macrophages through the NF-κB/NLRP3 signaling pathway. BMC Complement Med Ther 2023; 23:80. [PMID: 36906555 PMCID: PMC10007741 DOI: 10.1186/s12906-023-03902-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 02/28/2023] [Indexed: 03/13/2023] Open
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory disease of arterial wall, which is closely related to inflammatory reaction. In this study, the anti-inflammatory effect of isorhynchophylline was studied by NF- κB / NLRP3 pathway. METHODS (1) ApoE-/- mice were fed with high-fat diet to establish atherosclerotic model, while C57 with the same genetic background was fed with common diet as control group. Body weight was recorded and blood lipids were detected. The expression of NLRP3, NF-κB, IL-18 and Caspase-1 in aorta was detected by Western-Blot and PCR, and plaque formation was detected by HE and oil red O staining. (2) Lipopolysaccharide interfered with Human Umbilical Vein Endothelial Cells (HUVECs) and RAW264.7 to form inflammatory model, and was treated with isorhynchophylline. The expression of NLRP3, NF-κB, IL-18 and Caspase-1 in aorta was detected by Western-Blot and PCR, and the ability of cell migration was detected by Transwell and scratch test. RESULTS (1) the expression of NLRP3, NF- κB, IL-18 and Caspase-1 in aorta of model group was higher than that of control group, and plaque formation was obvious. (2) the expressions of NLRP3, NF- κB, IL-18 and Caspase-1 in HUVECs and RAW264.7 model groups were higher than those in control group, while isorhynchophylline decreased their expression and enhanced cell migration ability. CONCLUSION Isorhynchophylline can reduce the inflammatory reaction induced by lipopolysaccharide and promote the ability of cell migration.
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Keeter WC, Moriarty AK, Akers R, Ma S, Mussbacher M, Nadler JL, Galkina EV. Neutrophil-specific STAT4 deficiency attenuates atherosclerotic burden and improves plaque stability via reduction in neutrophil activation and recruitment into aortas of Ldlr -/- mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.22.529608. [PMID: 36865098 PMCID: PMC9980123 DOI: 10.1101/2023.02.22.529608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Background and Aims Neutrophils drive atheroprogression and directly contribute to plaque instability. We recently identified signal transducer and activator of transcription 4 (STAT4) as a critical component for bacterial host defense in neutrophils. The STAT4-dependent functions of neutrophils in atherogenesis are unknown. Therefore, we investigated a contributory role of STAT4 in neutrophils during advanced atherosclerosis. Methods We generated myeloid-specific Stat4 ΔLysM Ldlr -/- , neutrophil-specific Stat4 ΔS100A8 Ldlr -/- , and control Stat4 fl/fl Ldlr -/- mice. All groups were fed a high-fat/cholesterol diet (HFD-C) for 28 weeks to establish advanced atherosclerosis. Aortic root plaque burden and stability were assessed histologically by Movat Pentachrome staining. Nanostring gene expression analysis was performed on isolated blood neutrophils. Flow cytometry was utilized to analyze hematopoiesis and blood neutrophil activation. In vivo homing of neutrophils to atherosclerotic plaques was performed by adoptively transferring prelabeled Stat4 ΔLysM Ldlr -/- and Stat4 fl/fl Ldlr -/- bone marrow cells into aged atherosclerotic Apoe -/- mice and detected by flow cytometry. Results STAT4 deficiency in both myeloid-specific and neutrophil-specific mice provided similar reductions in aortic root plaque burden and improvements in plaque stability via reduction in necrotic core size, improved fibrous cap area, and increased vascular smooth muscle cell content within the fibrous cap. Myeloid-specific STAT4 deficiency resulted in decreased circulating neutrophils via reduced production of granulocyte-monocyte progenitors in the bone marrow. Neutrophil activation was dampened in Stat4 ΔLysM Ldlr -/- mice via reduced mitochondrial superoxide production, attenuated surface expression of degranulation marker CD63, and reduced frequency of neutrophil-platelet aggregates. Myeloid-specific STAT4 deficiency diminished expression of chemokine receptors CCR1 and CCR2 and impaired in vivo neutrophil trafficking to atherosclerotic aorta. Conclusions Our work indicates a pro-atherogenic role for STAT4-dependent neutrophil activation and how it contributes to multiple factors of plaque instability during advanced atherosclerosis in mice.
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Wakabayashi I. Associations between leukocyte count and lipid-related indices: Effect of age and confounding by habits of smoking and alcohol drinking. PLoS One 2023; 18:e0281185. [PMID: 36719880 PMCID: PMC9888682 DOI: 10.1371/journal.pone.0281185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 01/17/2023] [Indexed: 02/01/2023] Open
Abstract
Leukocyte count in peripheral blood is an acute-phase reactant and is associated with the risk of atherosclerotic diseases. Blood lipid profile, a major risk factor of cardiovascular disease, is known to be associated with leukocyte count, but it remains to be determined how this association is affected by other factors including lifestyle and age. The subjects were 11261 Japanese middle-aged men (30~65 years old) who had received health checkup examinations. The relationships of leukocyte count with lipid-related indices (ratio of LDL cholesterol to HDL cholesterol [LDL-C/HDL-C], ratio of triglycerides to HDL cholesterol [TG/HDL-C] and cardiometabolic index [CMI]) were investigated. Leukocyte count, LDL-C/HDL-C, TG/HDL-C and CMI were significantly higher in smokers than in nonsmokers, while leukocyte count and LDL-C/HDL-C were significantly lower in regular drinkers than in nondrinkers. Both in overall subjects and subjects without habits of smoking and drinking, LDL-C/HDL-C, TG/HDL-C and CMI were significantly higher in the 2nd and 3rd tertiles for leukocyte count than in the 1st tertile and tended to be higher with an increase of the tertile. Odds ratios for high TG/HDL-C and high CMI of the 3rd vs. 1st tertiles for leukocyte count tended to be lower with an increase of age, and odds ratios for high TG/HDL-C and high CMI of the interaction term, consisting of age (60~65 vs. 30~39 years) and tertile (3rd vs. 1st tertiles for leukocyte count), were significantly lower than the reference level. In conclusion, leukocyte count is associated with lipid-related indices, and the associations are independent of smoking and alcohol drinking and tend to be weaker with an increase of age in Japanese middle-aged men.
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Affiliation(s)
- Ichiro Wakabayashi
- Department of Environmental and Preventive Medicine, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
- * E-mail:
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19
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Zheng G, Zhao Y, Li Z, Hua Y, Zhang J, Miao Y, Guo Y, Li L, Shi J, Dong Z, Yang S, Fan G, Ma C. GLSP and GLSP-derived triterpenes attenuate atherosclerosis and aortic calcification by stimulating ABCA1/G1-mediated macrophage cholesterol efflux and inactivating RUNX2-mediated VSMC osteogenesis. Theranostics 2023; 13:1325-1341. [PMID: 36923537 PMCID: PMC10008734 DOI: 10.7150/thno.80250] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/14/2023] [Indexed: 03/13/2023] Open
Abstract
Background and Purpose: Atherosclerosis is the main pathophysiological foundation of cardiovascular disease, which was caused by inflammation and lipid metabolism disorder, along with vascular calcification. Aortic calcification leads to reduced plaque stability and eventually causes plaque rupture which leads to cardiovascular events. Presently, the drug to treat aortic calcification remains not to be available. Ganoderma lucidum spore powder (GLSP) is from Ganoderma lucidum which is a Traditional Chinese Medicine with the homology of medicine and food. It has multiple pharmacological effects, but no research on aortic calcification during atherosclerosis was performed. This study investigated the effects of GLSP on atherosclerosis and aortic calcification and revealed the underlying mechanism. Methods: In vivo, 8-week-aged male LDLR-/- mice were fed a high-fat diet to induce atherosclerosis along with aortic calcification. Simultaneously, the mice were treated with GLSP at the first week of HFD feeding to determine the protection against early and advanced atherosclerosis. Subsequently, the mice tissues were collected to evaluate the effects of GLSP on atherosclerosis, and aortic calcification, and to reveal the underlying mechanism. In vitro, we determined the major components of GLSP triterpenes by HPLC, and subsequently assessed the protective effects of these main active components on lipid metabolism, inflammation, and calcification in RAW264.7 and HASMC cells. Results: We observed GLSP attenuated plaque area and aortic calcification in the mice with early and advanced atherosclerosis. GLSP reduced the number of foam cells by improving ABCA1/G1-mediated cholesterol efflux in macrophages. In addition, GLSP protected against the aortic endothelium activation. Moreover, GLSP inhibited aortic calcification by inactivating RUNX2-mediated osteogenesis in HASMCs. Furthermore, we determined the major components of GLSP triterpenes, including Ganoderic acid A, Ganoderic acid B, Ganoderic acid C6, Ganoderic acid G, and Ganodermanontriol, and found that these triterpenes promoted ABCA1/G1-mediated cholesterol efflux and inhibited inflammation in macrophage, and inactivated RUNX2-mediated osteogenesis in VSMC. Conclusions: This study demonstrates that GLSP attenuates atherosclerosis and aortic calcification by improving ABCA1/G1-mediated cholesterol efflux and inactivating RUNX2-mediated osteogenesis in LDLR-/- mice. GLSP may be a potential drug candidate for the treatment of atherosclerosis and vascular calcification.
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Affiliation(s)
- Guobin Zheng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China
| | - Yun Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhenhao Li
- Zhejiang ShouXianGu Botanical Drug Institute, Zhejiang Hangzhou 321200 China
| | - Yunqing Hua
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jing Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yaodong Miao
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, P. R. China
| | - Yang Guo
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Lan Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jia Shi
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhengwei Dong
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shu Yang
- Department of Geriatrics, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China
| | - Guanwei Fan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Chuanrui Ma
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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20
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Fang F, Xiao C, Li C, Liu X, Li S. Tuning macrophages for atherosclerosis treatment. Regen Biomater 2022; 10:rbac103. [PMID: 36683743 PMCID: PMC9845526 DOI: 10.1093/rb/rbac103] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 11/18/2022] [Accepted: 12/02/2022] [Indexed: 12/15/2022] Open
Abstract
Atherosclerosis is a chronic inflammatory vascular disease and a leading cause of death worldwide. Macrophages play an important role in inflammatory responses, cell-cell communications, plaque growth and plaque rupture in atherosclerotic lesions. Here, we review the sources, functions and complex phenotypes of macrophages in the progression of atherosclerosis, and discuss the recent approaches in modulating macrophage phenotype and autophagy for atherosclerosis treatment. We then focus on the drug delivery strategies that target macrophages or use macrophage membrane-coated particles to deliver therapeutics to the lesion sites. These biomaterial-based approaches that target, modulate or engineer macrophages have broad applications for disease therapies and tissue regeneration.
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Affiliation(s)
- Fei Fang
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, USA
- Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Crystal Xiao
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, USA
- Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Chunli Li
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Xiaoheng Liu
- Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Song Li
- Department of Bioengineering, University of California, Los Angeles, Los Angeles, California 90095, USA
- Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA
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21
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Savla SR, Prabhavalkar KS, Bhatt LK. Liver X Receptor: a potential target in the treatment of atherosclerosis. Expert Opin Ther Targets 2022; 26:645-658. [PMID: 36003057 DOI: 10.1080/14728222.2022.2117610] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Liver X receptors (LXRs) are master regulators of atherogenesis. Their anti-atherogenic potential has been attributed to their role in the inhibition of macrophage-mediated inflammation and promotion of reverse cholesterol transport. Owing to the significance of their anti-atherogenic potential, it is essential to develop and test new generation LXR agonists, both synthetic and natural, to identify potential LXR-targeted therapeutics for the future. AREAS COVERED This review describes the role of LXRs in atherosclerotic development, provides a summary of LXR agonists and future directions for atherosclerosis research. We searched PubMed, Scopus and Google Scholar for relevant reports, from last 10 years, using atherosclerosis, liver X receptor, and LXR agonist as keywords. EXPERT OPINION LXRα has gained widespread recognition as a regulator of cholesterol homeostasis and expression of inflammatory genes. Further research using models of cell type-specific knockout and specific agonist-targeted LXR isoforms is warranted. Enthusiasm for therapeutic value of LXR agonists has been tempered due to LXRα-mediated induction of hepatic lipogenesis. LXRα agonism and LXRβ targeting, gut-specific inverse LXR agonists, investigations combining LXR agonists with other lipogenesis mitigating agents, like IDOL antagonists and synthetic HDL, and targeting ABCA1, M2 macrophages and LXRα phosphorylation, remain as promising possibilities.
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Affiliation(s)
- Shreya R Savla
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai 400056, India
| | - Kedar S Prabhavalkar
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai 400056, India
| | - Lokesh K Bhatt
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai 400056, India
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22
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Stahr N, Galkina EV. Immune Response at the Crossroads of Atherosclerosis and Alzheimer's Disease. Front Cardiovasc Med 2022; 9:870144. [PMID: 35872901 PMCID: PMC9298512 DOI: 10.3389/fcvm.2022.870144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 06/02/2022] [Indexed: 11/30/2022] Open
Abstract
Alzheimer's disease (AD) and cardiovascular disease (CVD) are pathologies that are characterized by common signatures of vascular dysfunction and chronic inflammation that are accelerated with aging. Importantly, epidemiological studies report an independent interaction between AD and CVD and data suggest that chronic inflammation in CVD may accelerate AD development. Atherosclerosis affects most large to medium sized arteries including those supplying the cerebral circulation. Vascular dysfunction caused by atherosclerosis results in blood brain barrier breakdown, inflammation, an impaired clearance of amyloid-beta (Aβ), and finally ends with neurovascular dysfunction. Numerous data indicate that innate and adaptive immune responses shape atherogenesis and increasing evidence suggests an implication of the immune response in AD progression. Currently, mechanisms by which these two diseases are interconnected with each other are not well-defined. In this review, we discuss the recent advances in our understanding of the intertwined role of the immune response in atherosclerosis and AD and the implications of these findings for human health.
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23
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Fernández-García V, González-Ramos S, Avendaño-Ortiz J, Martín-Sanz P, Gómez-Coronado D, Delgado C, Castrillo A, Boscá L. High-fat diet activates splenic NOD1 and enhances neutrophil recruitment and neutrophil extracellular traps release in the spleen of ApoE-deficient mice. Cell Mol Life Sci 2022; 79:396. [PMID: 35789437 PMCID: PMC9256580 DOI: 10.1007/s00018-022-04415-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 05/19/2022] [Accepted: 06/03/2022] [Indexed: 12/14/2022]
Abstract
In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis, and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells, as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed on a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe-/- and Apoe-/-Nod1-/- mice fed on HFD for 4 weeks were used. Splenic NOD1 from Apoe-/- mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe-/-Nod1-/- mice. Indeed, the presence of Ly6G+ cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe-/- counterparts, which suggests that the mobilization and activation of circulating immune cells are altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe-/-Nod1-/- mice showed a reduced atherogenic disease, and diminished recruitment of neutrophils in the spleen, compared to Apoe-/- mice. However, splenic artery ligation reduced the atherogenic burden in Apoe-/- mice an effect that, unexpectedly was lost in Apoe-/-Nod1-/- mice. Together, these results suggest that neutrophil accumulation and activity in the spleen are driven in part by NOD1 activation in mice fed on HFD, contributing in this way to regulating atherogenic progression.
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Affiliation(s)
- Victoria Fernández-García
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Monforte de Lemos 3-5, 28029, Madrid, Spain.
| | - Silvia González-Ramos
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
| | - José Avendaño-Ortiz
- Instituto de Investigación Sanitaria del Hospital Universitario La Paz, IdiPAZ., C. de Pedro Rico, 6, 28029, Madrid, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Diego Gómez-Coronado
- Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, Ctra. M-607 9,100, 28034, Madrid, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Carmen Delgado
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Monforte de Lemos 3-5, 28029, Madrid, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain
- Unidad de Biomedicina (Unidad Asociada Al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029, Madrid, Spain.
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Monforte de Lemos 3-5, 28029, Madrid, Spain.
- Unidad de Biomedicina (Unidad Asociada Al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
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24
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Jenkins AJ, Grant MB, Busik JV. Lipids, hyperreflective crystalline deposits and diabetic retinopathy: potential systemic and retinal-specific effect of lipid-lowering therapies. Diabetologia 2022; 65:587-603. [PMID: 35149880 PMCID: PMC9377536 DOI: 10.1007/s00125-022-05655-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 12/14/2021] [Indexed: 12/19/2022]
Abstract
The metabolically active retina obtains essential lipids by endogenous biosynthesis and from the systemic circulation. Clinical studies provide limited and sometimes conflicting evidence as to the relationships between circulating lipid levels and the development and progression of diabetic retinopathy in people with diabetes. Cardiovascular-system-focused clinical trials that also evaluated some retinal outcomes demonstrate the potential protective power of lipid-lowering therapies in diabetic retinopathy and some trials with ocular primary endpoints are in progress. Although triacylglycerol-lowering therapies with fibrates afforded some protection against diabetic retinopathy, the effect was independent of changes in traditional blood lipid classes. While systemic LDL-cholesterol lowering with statins did not afford protection against diabetic retinopathy in most clinical trials, and none of the trials focused on retinopathy as the main outcome, data from very large database studies suggest the possible effectiveness of statins. Potential challenges in these studies are discussed, including lipid-independent effects of fibrates and statins, modified lipoproteins and retinal-specific effects of lipid-lowering drugs. Dysregulation of retinal-specific cholesterol metabolism leading to retinal cholesterol accumulation and potential formation of cholesterol crystals are also addressed.
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Affiliation(s)
- Alicia J Jenkins
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - Maria B Grant
- Department of Ophthalmology and Vision Science, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Julia V Busik
- Department of Physiology, Michigan State University, East Lansing, MI, USA.
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25
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Kremastiotis G, Handa I, Jackson C, George S, Johnson J. Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis. Sci Rep 2021; 11:23081. [PMID: 34848763 PMCID: PMC8632906 DOI: 10.1038/s41598-021-02508-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/12/2021] [Indexed: 11/12/2022] Open
Abstract
Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.
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Affiliation(s)
- Georgios Kremastiotis
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Ishita Handa
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Christopher Jackson
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Sarah George
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Jason Johnson
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK.
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26
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Hong S, Nagayach A, Lu Y, Peng H, Duong QVA, Pham NB, Vuong CA, Bazan NG. A high fat, sugar, and salt Western diet induces motor-muscular and sensory dysfunctions and neurodegeneration in mice during aging: Ameliorative action of metformin. CNS Neurosci Ther 2021; 27:1458-1471. [PMID: 34510763 PMCID: PMC8611779 DOI: 10.1111/cns.13726] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 01/18/2023] Open
Abstract
Aims To explore the novel linkage between a Western diet combining high saturated fat, sugar, and salt (HFSS) and neurological dysfunctions during aging as well as Metformin intervention, we assessed cerebral cortex abnormalities associated with sensory and motor dysfunctions and cellular and molecular insights in brains using HFSS‐fed mice during aging. We also explored the effect of Metformin treatment on these mice. Methods C57BL/6 mice were fed with HFSS and treated with metformin from 20 to 22 months of age, resembling human aging from 56 to 68 years of age (an entry phase of the aged portion of lifespan). Results The motor and sensory cortexes in mice during aging after HFSS diet showed: (A) decreased motor‐muscular and sensory functions; (B) reduced inflammation‐resolving Arg‐1+ microglia; (C) increased inflammatory iNOs+ microglia and TNFα levels; (D) enhanced abundance of amyloid‐β peptide and of phosphorylated Tau. Metformin attenuated these changes. Conclusion A HFSS‐combined diet caused motor‐muscular and sensory dysfunctions, neuroinflammation, and neurodegeneration, whereas metformin counteracted these effects. Our findings show neuroinflammatory consequences of a HFSS diet in aging. Metformin curbs the HFSS‐related neuroinflammation eliciting neuroprotection.
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Affiliation(s)
- Song Hong
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.,Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Aarti Nagayach
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Yan Lu
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Hongying Peng
- Biostatistics, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Quoc-Viet A Duong
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Nicholas B Pham
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Christopher A Vuong
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.,Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
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27
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Han J, Zhang R, Zhang X, Dong J, Chen M, Pan Y, Liao Z, Zhong M, He J, Wang F, Yue Y, Shang J. Zebrafish Model for Screening Antiatherosclerosis Drugs. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9995401. [PMID: 34257830 PMCID: PMC8245221 DOI: 10.1155/2021/9995401] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 05/23/2021] [Indexed: 01/30/2023]
Abstract
This study is aimed at establishing a zebrafish model of AS, which can be applied for high-throughput screening anti-AS drugs. A zebrafish AS model was induced by high cholesterol diet (HCD) and lipopolysaccharide (LPS). In the early stage of modeling, HCD induced zebrafish to show some early symptoms similar to human AS, mainly cholesterol accumulation, vascular inflammation, lipid metabolism disorder, and oxidative stress. In addition to lipid metabolism disorders, LPS also induced the same symptoms. And when HCD and LPS exist at the same time, these AS symptoms in zebrafish become more severe. When the modeling time reached 45 days, HCD and LPS induce the formation of plaques in zebrafish blood vessels, and these plaques contain fibrous tissue and lipids, which are similar to human AS plaques. We also evaluated the efficacy of some anti-AS drugs (atorvastatin, aspirin, and vitamin C) through these zebrafish AS models. The results found that atorvastatin can significantly reduce the symptoms of AS induced by HCD and LPS, and aspirin and vitamins can significantly reduce the symptoms of AS induced by LPS. It is feasible to use zebrafish to establish an AS model, and the zebrafish AS model can be used for high-throughput screening of anti-AS drugs.
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Affiliation(s)
- Jichun Han
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Rui Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Xiaofeng Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Jing Dong
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Minghan Chen
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Yumin Pan
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Zixian Liao
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Min Zhong
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Jingwen He
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Feiqiang Wang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Yunyun Yue
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
| | - Jing Shang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198 Jiangsu, China
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Wu B, You S, Qian H, Wu S, Lu S, Zhang Y, Sun Y, Zhang N. The role of SIRT2 in vascular-related and heart-related diseases: A review. J Cell Mol Med 2021; 25:6470-6478. [PMID: 34028177 PMCID: PMC8278089 DOI: 10.1111/jcmm.16618] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/01/2021] [Accepted: 04/13/2021] [Indexed: 12/15/2022] Open
Abstract
At present, cardiovascular disease is one of the important factors of human death, and there are many kinds of proteins involved. Sirtuins family proteins are involved in various physiological and pathological activities of the human body. Among them, there are more and more studies on the relationship between sirtuin2 (SIRT2) protein and cardiovascular diseases. SIRT2 can effectively inhibit pathological cardiac hypertrophy. The effect of SIRT2 on ischaemia‐reperfusion injury has different effects under different conditions. SIRT2 can reduce the level of reactive oxygen species (ROS), which may help to reduce the severity of diabetic cardiomyopathy. SIRT2 can affect a variety of cardiovascular diseases, energy metabolism and the ageing of cardiomyocytes, thereby affecting heart failure. SIRT2 also plays an important role in vascular disease. For endothelial cell damage used by oxidative stress, the role of SIRT2 is bidirectional, which is related to the degree of oxidative stress stimulation. When the degree of stimulation is small, SIRT2 plays a protective role, and when the degree of stimulation increases to a certain level, SIRT2 plays a negative role. In addition, SIRT2 is also involved in the remodelling of blood vessels and the repair of skin damage.
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Affiliation(s)
- Boquan Wu
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Shilong You
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Hao Qian
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Shaojun Wu
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Saien Lu
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Ying Zhang
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Yingxian Sun
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
| | - Naijin Zhang
- Department of Cardiology, The First Hospital of China Medical University, Shenyang, China
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Winn NC, Cottam MA, Wasserman DH, Hasty AH. Exercise and Adipose Tissue Immunity: Outrunning Inflammation. Obesity (Silver Spring) 2021; 29:790-801. [PMID: 33899336 DOI: 10.1002/oby.23147] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/02/2021] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Chronic inflammation is considered a precipitating factor and possibly an underlying cause of many noncommunicable diseases, including cardiovascular disease, metabolic diseases, and some cancers. Obesity, which manifests in more than 650 million people worldwide, is the most common chronic inflammatory condition, with visceral adiposity thought to be the major inflammatory hub that links obesity and chronic disease. Adipose tissue (AT) inflammation is triggered or heightened in large part by (1) accelerated immune cell recruitment, (2) reshaping of the AT stromal-immuno landscape (e.g., immune cells, endothelial cells, fibroblasts, adipocyte progenitors), and (3) perturbed AT immune cell function. Exercise, along with diet management, is a cornerstone in promoting weight loss and preventing weight regain. This review focuses on evidence that increased physical activity reduces AT inflammation caused by hypercaloric diets or genetic obesity. The precise cell types and mechanisms responsible for the therapeutic effects of exercise on AT inflammation remain poorly understood. This review summarizes what is known about obesity-induced AT inflammation and immunomodulation and highlights mechanisms by which aerobic exercise combats inflammation by remodeling the AT immune landscape. Furthermore, key areas are highlighted that require future exploration and novel discoveries into the burgeoning field of how the biology of exercise affects AT immunity.
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Affiliation(s)
- Nathan C Winn
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - Matthew A Cottam
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- Vanderbilt Mouse Metabolic Phenotyping Center, Nashville, Tennessee, USA
| | - Alyssa H Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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30
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Role of macrophage autophagy in atherosclerosis: modulation by bioactive compounds. Biochem J 2021; 478:1359-1375. [PMID: 33861844 DOI: 10.1042/bcj20200894] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/28/2022]
Abstract
Atherosclerosis is a chronic inflammatory disease associated with lipid metabolism disorder. Autophagy is a catabolic process and contributes to maintaining cellular homeostasis. Substantial evidence suggests that defective autophagy is implicated in several diseases, including atherosclerosis, while increased autophagy mitigates atherosclerosis development. Thus, understanding the mechanisms of autophagy regulation and its association with atherosclerosis is vital to develop new therapies against atherosclerosis. Dietary bioactive compounds are non-nutrient natural compounds that include phenolics, flavonoids, and carotenoids. Importantly, these bioactive compounds possess anti-inflammatory, antioxidant, and antibacterial properties that may alleviate various chronic diseases. Recently, examining the effects of bioactive compounds on autophagy activity in atherogenesis has drawn considerable attention. The current review discusses the role of macrophage autophagy in the development and progression of atherosclerosis. We also summarize our current knowledge of the therapeutic potential of bioactive compounds on atherosclerosis and autophagy.
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Viaud M, Abdel-Wahab O, Gall J, Ivanov S, Guinamard R, Sore S, Merlin J, Ayrault M, Guilbaud E, Jacquel A, Auberger P, Wang N, Levine RL, Tall AR, Yvan-Charvet L. ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms. Cell Rep 2021; 30:3397-3410.e5. [PMID: 32160545 PMCID: PMC7473128 DOI: 10.1016/j.celrep.2020.02.056] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 11/23/2019] [Accepted: 02/12/2020] [Indexed: 12/13/2022] Open
Abstract
Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia (CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis. Viaud et al. show that ABCA1 mutants identified in CMML patients diminish the tumor-suppressor functions of ABCA1 and cooperate with Tet2 loss to confer the hypersensitivity of myeloid progenitors to IL-3 receptor β canonical signaling, which can be prevented by raising HDL levels.
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Affiliation(s)
- Manon Viaud
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Omar Abdel-Wahab
- Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Julie Gall
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Stoyan Ivanov
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Rodolphe Guinamard
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Sophie Sore
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Johanna Merlin
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Marion Ayrault
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Emma Guilbaud
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Arnaud Jacquel
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Patrick Auberger
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France
| | - Nan Wang
- Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Ross L Levine
- Human Oncology and Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Alan R Tall
- Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Laurent Yvan-Charvet
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1065, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire (C3M), Atip-Avenir, Fédération Hospitalo-Universitaire (FHU) Oncoage, 06204 Nice, France.
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Tucker B, Sawant S, McDonald H, Rye KA, Patel S, Ong KL, Cochran BJ. The association of serum lipid and lipoprotein levels with total and differential leukocyte counts: Results of a cross-sectional and longitudinal analysis of the UK Biobank. Atherosclerosis 2020; 319:1-9. [PMID: 33453490 DOI: 10.1016/j.atherosclerosis.2020.12.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 12/15/2020] [Accepted: 12/18/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIMS There is some evidence of a cross-sectional, and possibly causal, relationship of lipid levels with leukocyte counts in mice and humans. This study investigates the cross-sectional and longitudinal relationship of blood lipid and lipoprotein levels with leukocyte counts in the UK Biobank cohort. METHODS The primary cross-sectional analysis included 417,132 participants with valid data on lipid measures and leukocyte counts. A subgroup analysis was performed in 333,668 participants with valid data on lipoprotein(a). The longitudinal analysis included 9058 participants with valid baseline and follow-up data on lipid and lipoprotein levels and leukocyte counts. The association of lipid and lipoprotein levels with leukocyte counts was analysed by multivariable linear regression. RESULTS Several relationships were significant in both cross-sectional and longitudinal analysis. After adjustment for demographic, socioeconomic and other confounding factors, a higher eosinophil count was associated with lower HDL cholesterol and apolipoprotein A-I concentration (p < 0.001). Higher triglycerides levels were associated with higher total leukocyte, basophil, eosinophil, monocyte and neutrophil counts (all p < 0.01). A higher lymphocyte count was associated with a higher apolipoprotein B level (p < 0.001). In the longitudinal analysis, lipoprotein(a) was inversely associated with basophil count in men but not women (p < 0.001). CONCLUSIONS Triglyceride levels demonstrate a robust positive association with total and differential leukocyte counts suggesting they may be directly involved in leukogenesis. However, unlike in murine models, the remainder of these relationships is modest, which suggests that cholesterol and lipoproteins are minimally involved in leukogenesis in humans.
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Affiliation(s)
- Bradley Tucker
- Heart Research Institute, Sydney, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, Australia; School of Medical Sciences, UNSW, Sydney, Australia
| | | | | | | | - Sanjay Patel
- Heart Research Institute, Sydney, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Royal Prince Alfred Hospital, Sydney, Australia
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Chang TI, Wu X, Boström KI, Tran HA, Couto-Souza PH, Friedlander AH. Elevated White Blood Cell Count Resultant Atherogenesis is Associated With Panoramic-Imaged Carotid Plaque. J Oral Maxillofac Surg 2020; 79:1069-1073. [PMID: 33290724 DOI: 10.1016/j.joms.2020.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/10/2020] [Accepted: 11/10/2020] [Indexed: 11/30/2022]
Abstract
PURPOSE Atherosclerotic plaques develop as a result of a low-grade, chronic, systemic inflammatory response to the injury of endothelial cells arising from lipid deposition within the intima. Increased white blood cell count (WBCC) is both a validated "biologic marker" of the extent of this inflammatory process and a key participant in the development of subsequent atherosclerotic ischemic heart disease manifesting as myocardial infarction. We sought to determine if calcified carotid artery plaque (CCAP) on a panoramic image (PI), also a validated risk indicator of future myocardial infarction, is associated with increased WBCC. PATIENTS AND METHODS We retrospectively evaluated the PI and medical records of White male military veterans aged 55 years and older treated by a VA dental service. Established were 2 cohorts of patients, 50 having plaques (CCAP+) and 50 without plaques (CCAP-). Predictor variable was CCAP+; outcome variable was WBCC. Bootstrapping analysis determined the differences in mean WBCCs between groups. Statistical significance set at ≤ 0.05. RESULTS The study group, (mean age 74; range 59 to 91 years) demonstrated a mean WBCC of 8,062 per mm3. The control group, (mean age 72 range; 57 to 94) evidenced a mean WBCC of 7,058 per mm3. Bootstrapping analysis of WBCC values demonstrated a significant (P = .012) difference (95% confidence interval of difference of mean, -806, 742; observed effect size, 1004) between groups. CONCLUSIONS The presence of CCAP demonstrated on PIs of older Caucasian men is associated with elevated WBCC. Concomitant presence of CCAP on PI and increased WBCC (≥7,800 per mm3) amplifies need for medical consultation before intravenous anesthesia and maxillofacial surgical procedures.
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Affiliation(s)
- Tina I Chang
- Director, Inpatient Oral and Maxillofacial Surgery at the Veterans Affairs Great Los Angeles Healthcare System and an Instructor in Oral and Maxillofacial Surgery, School of Dentistry, University of California, Los Angeles, CA
| | - Xiuju Wu
- Project Scientist, Division of Cardiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA
| | - Kristina I Boström
- Chief of Cardiology, VA Greater Los Angeles Healthcare System and Professor of Medicine/Cardiology, David Geffen School of Medicine at UCLA and at the Molecular Biology Institute, University of California, Los Angeles, CA
| | - Hoang-Anh Tran
- Periodontology Resident, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA
| | - Paulo H Couto-Souza
- Professor, Maxillofacial Radiology, Graduate Program in Dentistry/School of Life Sciences, Pontifícia Universidade Católica do Paraná, Curitiba, Paraná, Brazil
| | - Arthur H Friedlander
- Associate Chief of Staff and Director ofGraduate Medical Education, Veterans Affairs Greater Los Angeles Healthcare System, and Director of, Quality Assurance Hospital Dental Service, Ronald Reagan UCLA Medical Center and Professor-in-Residence of Oral and Maxillofacial Surgery, School of Dentistry, University of California, Los Angeles, CA.
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Fernández-García V, González-Ramos S, Martín-Sanz P, Castrillo A, Boscá L. Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells. Front Immunol 2020; 11:586527. [PMID: 33193412 PMCID: PMC7649205 DOI: 10.3389/fimmu.2020.586527] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 10/06/2020] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular diseases (CVDs) incidence is becoming higher. This fact is promoted by metabolic disorders such as obesity, and aging. Atherosclerosis is the underlying cause of most of these pathologies. It is a chronic inflammatory disease that begins with the progressive accumulation of lipids and fibrotic materials in the blood-vessel wall, which leads to massive leukocyte recruitment. Rupture of the fibrous cap of the atherogenic cusps is responsible for tissue ischemic events, among them myocardial infarction. Extramedullary hematopoiesis (EMH), or blood cell production outside the bone marrow (BM), occurs when the normal production of these cells is impaired (chronic hematological and genetic disorders, leukemia, etc.) or is altered by metabolic disorders, such as hypercholesterolemia, or after myocardial infarction. Recent studies indicate that the main EMH tissues (spleen, liver, adipose and lymph nodes) complement the hematopoietic function of the BM, producing circulating inflammatory cells that infiltrate into the atheroma. Indeed, the spleen, which is a secondary lymphopoietic organ with high metabolic activity, contains a reservoir of myeloid progenitors and monocytes, constituting an important source of inflammatory cells to the atherosclerotic lesion. Furthermore, the spleen also plays an important role in lipid homeostasis and immune-cell selection. Interestingly, clinical evidence from splenectomized subjects shows that they are more susceptible to developing pathologies, such as dyslipidemia and atherosclerosis due to the loss of immune selection. Although CVDs represent the leading cause of death worldwide, the mechanisms involving the spleen-atherosclerosis-heart axis cross-talk remain poorly characterized.
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Affiliation(s)
- Victoria Fernández-García
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Silvia González-Ramos
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
- Unidad de Biomedicina, (Unidad Asociada al CSIC), Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM) and Universidad de Las Palmas, Gran Canaria, Spain
- Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Grupo de Investigación Medio Ambiente y Salud, Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Madrid, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Unidad de Biomedicina, (Unidad Asociada al CSIC), Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM) and Universidad de Las Palmas, Gran Canaria, Spain
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Aguilar-Ballester M, Herrero-Cervera A, Vinué Á, Martínez-Hervás S, González-Navarro H. Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis. Nutrients 2020; 12:nu12072021. [PMID: 32645995 PMCID: PMC7400846 DOI: 10.3390/nu12072021] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 06/29/2020] [Accepted: 07/02/2020] [Indexed: 12/24/2022] Open
Abstract
Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, cholesterol levels also play important roles in immune cells such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.
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Affiliation(s)
- María Aguilar-Ballester
- INCLIVA Institute of Health Research, 46010 Valencia, Spain; (M.A.-B.); (A.H.-C.); (Á.V.); (S.M.-H.)
| | - Andrea Herrero-Cervera
- INCLIVA Institute of Health Research, 46010 Valencia, Spain; (M.A.-B.); (A.H.-C.); (Á.V.); (S.M.-H.)
| | - Ángela Vinué
- INCLIVA Institute of Health Research, 46010 Valencia, Spain; (M.A.-B.); (A.H.-C.); (Á.V.); (S.M.-H.)
| | - Sergio Martínez-Hervás
- INCLIVA Institute of Health Research, 46010 Valencia, Spain; (M.A.-B.); (A.H.-C.); (Á.V.); (S.M.-H.)
- Endocrinology and Nutrition Department Clinic Hospital and Department of Medicine, University of Valencia, 46010 Valencia, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Herminia González-Navarro
- INCLIVA Institute of Health Research, 46010 Valencia, Spain; (M.A.-B.); (A.H.-C.); (Á.V.); (S.M.-H.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
- Department of Didactics of Experimental and Social Sciences, University of Valencia, 46010 Valencia, Spain
- Correspondence: ; Tel.: +34-963864403; Fax: +34-963987860
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The Research Progress of Vascular Macrophages and Atherosclerosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:7308736. [PMID: 32566098 PMCID: PMC7267869 DOI: 10.1155/2020/7308736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/09/2020] [Accepted: 03/25/2020] [Indexed: 02/05/2023]
Abstract
Materials We made a minireview on the association of vascular macrophages with AS based on recent research studies systematically, from the mechanisms of macrophages accumulating in the walls of blood vessels, and the role of macrophages in AS as well as microenvironmental determinants of macrophage function in AS. The discovery of these mechanisms could reveal the pathogenesis of AS comprehensively and is crucial to provide scientific evidence for formulating the related measures of prevention and treatment for AS. Discussion. Vascular macrophages play important roles in the development of AS, and the vascular macrophages may become new targets for the prevention and treatment of AS. Effective regulation of host genes may help prevent or even treat AS. Conclusion This minireview focuses on the association of vascular macrophages with the development of AS, which may supply some clues for future therapies and novel drug targets for AS.
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Wang Y, Jia A, Bi Y, Wang Y, Liu G. Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer. Cells 2020; 9:cells9041011. [PMID: 32325683 PMCID: PMC7226088 DOI: 10.3390/cells9041011] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/15/2020] [Accepted: 04/16/2020] [Indexed: 02/06/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a group of immunosuppressive cells that play crucial roles in promoting tumor growth and protecting tumors from immune recognition in tumor-bearing mice and cancer patients. Recently, it has been shown that the metabolic activity of MDSCs plays an important role in the regulation of their inhibitory function, especially in the processes of tumor occurrence and development. The MDSC metabolism, such as glycolysis, fatty acid oxidation and amino acid metabolism, is rewired in the tumor microenvironment (TME), which enhances the immunosuppressive activity, resulting in effector T cell apoptosis and suppressive cell proliferation. Herein, we summarized the recent progress in the metabolic reprogramming and immunosuppressive function of MDSCs during tumorigenesis.
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Affiliation(s)
- Yufei Wang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (Y.W.); (A.J.); (Y.W.)
| | - Anna Jia
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (Y.W.); (A.J.); (Y.W.)
| | - Yujing Bi
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China;
| | - Yuexin Wang
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (Y.W.); (A.J.); (Y.W.)
| | - Guangwei Liu
- Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China; (Y.W.); (A.J.); (Y.W.)
- Correspondence: ; Tel./Fax: +86-10-58800026
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Taghizadeh E, Taheri F, Gheibi Hayat SM, Montecucco F, Carbone F, Rostami D, Montazeri A, Sahebkar A. The atherogenic role of immune cells in familial hypercholesterolemia. IUBMB Life 2020; 72:782-789. [PMID: 31633867 DOI: 10.1002/iub.2179] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 09/16/2019] [Indexed: 12/19/2022]
Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism that mainly occurs due to mutations in the low-density lipoprotein receptor gene and is characterized by increased levels of low-density lipoprotein cholesterol, leading to accelerated atherogenesis and premature coronary heart disease. Both innate and adaptive immune responses, which mainly include monocytes, macrophages, neutrophils, T lymphocytes, and B lymphocytes, have been shown to play a key role for the initiation and progression of atherogenesis in the general population. In FH patients, these immune cells have been suggested to play specific pro-atherosclerotic activities, from the initial leukocyte recruitment to plaque rupture. In fact, the accumulation of cholesterol crystals and oxLDL in the vessels in FH patients is particularly high, with consequent abnormal mobilization of immune cells and secretion of various pro-inflammatory and chemokines. In addition, cholesterol accumulation in immune cells is exaggerated with chronic exposure to relevant pro-atherosclerotic triggers. The topics considered in this review may provide a more specific focus on the immune system alterations in FH and open new insights toward immune cells as potential therapeutic targets in FH.
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Affiliation(s)
- Eskandar Taghizadeh
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine, and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
- First Clinic of Internal Medicine, IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, IRCCS Ospedale Policlinico San Martino Genoa-Italian Cardiovascular Network, Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Daryoush Rostami
- Department of School Allied, Zabol University of Medical Sciences, Zabol, Iran
| | - Ardalan Montazeri
- Department of Biology, Faculty of Science, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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39
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Mayneris-Perxachs J, Puig J, Burcelin R, Dumas ME, Barton RH, Hoyles L, Federici M, Fernández-Real JM. The APOA1bp-SREBF-NOTCH axis is associated with reduced atherosclerosis risk in morbidly obese patients. Clin Nutr 2020; 39:3408-3418. [PMID: 32199697 DOI: 10.1016/j.clnu.2020.02.034] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/23/2020] [Accepted: 02/24/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND & AIMS Atherosclerosis is characterized by an inflammatory disease linked to excessive lipid accumulation in the artery wall. The Notch signalling pathway has been shown to play a key regulatory role in the regulation of inflammation. Recently, in vitro and pre-clinical studies have shown that apolipoprotein A-I binding protein (AIBP) regulates cholesterol metabolism (SREBP) and NOTCH signalling (haematopoiesis) and may be protective against atherosclerosis, but the evidence in humans is scarce. METHODS We evaluated the APOA1bp-SREBF-NOTCH axis in association with atherosclerosis in two well-characterized cohorts of morbidly obese patients (n = 78) within the FLORINASH study, including liver transcriptomics, 1H NMR plasma metabolomics, high-resolution ultrasonography evaluating carotid intima-media thickness (cIMT), and haematological parameters. RESULTS The liver expression levels of APOA1bp were associated with lower cIMT and leukocyte counts, a better plasma lipid profile and higher circulating levels of metabolites associated with lower risk of atherosclerosis (glycine, histidine and asparagine). Conversely, liver SREBF and NOTCH mRNAs were positively associated with atherosclerosis, liver steatosis, an unfavourable lipid profile, higher leukocytes and increased levels of metabolites linked to inflammation and CVD such as branched-chain amino acids and glycoproteins. APOA1bp and NOTCH signalling also had a strong association, as revealed by the negative correlations among APOA1bp expression levels and those of all NOTCH receptors and jagged ligands. CONCLUSIONS We here provide the first evidence in human liver of the putative APOA1bp-SREBF-NOTCH axis signalling pathway and its association with atherosclerosis and inflammation.
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Affiliation(s)
- Jordi Mayneris-Perxachs
- Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain; CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain
| | - Josep Puig
- Department of Radiology, Diagnostic Imaging Institute (IDI), Dr Josep Trueta University Hospital, IDIBGI, Girona, Spain
| | - Rémy Burcelin
- Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France; Université Paul Sabatier (UPS), Unité Mixte de Recherche (UMR) 1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Team 2: 'Intestinal Risk Factors, Diabetes, Dyslipidemia, and Heart Failure', F-31432 Toulouse Cedex 4, France
| | - Marc-Emmanuel Dumas
- Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom; Section of Genomic and Environmental Medicine, Respiratory Division, National Heart and Lung Institute, Imperial College London, Dovehouse St, London SW3 6KY, United Kingdom
| | - Richard H Barton
- Section of Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom
| | - Lesley Hoyles
- Department of Biosciences, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, United Kingdom
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - José-Manuel Fernández-Real
- Department of Endocrinology, Diabetes and Nutrition, Hospital of Girona "Dr Josep Trueta", Departament de Ciències Mèdiques, University of Girona, Girona Biomedical Research Institute (IdibGi), Girona, Spain; CIBERobn Pathophysiology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain.
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40
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Hu C, Pang B, Lin G, Zhen Y, Yi H. Energy metabolism manipulates the fate and function of tumour myeloid-derived suppressor cells. Br J Cancer 2020; 122:23-29. [PMID: 31819182 PMCID: PMC6964679 DOI: 10.1038/s41416-019-0644-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 10/23/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
In recent years, a large number of studies have been carried out in the field of immune metabolism, highlighting the role of metabolic energy reprogramming in altering the function of immune cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells generated during a large array of pathological conditions, such as cancer, inflammation, and infection, and show remarkable ability to suppress T-cell responses. These cells can also change their metabolic pathways in response to various pathogen-derived or inflammatory signals. In this review, we focus on the roles of glucose, fatty acid (FA), and amino acid (AA) metabolism in the differentiation and function of MDSCs in the tumour microenvironment, highlighting their potential as targets to inhibit tumour growth and enhance tumour immune surveillance by the host. We further highlight the remaining gaps in knowledge concerning the mechanisms determining the plasticity of MDSCs in different environments and their specific responses in the tumour environment. Therefore, this review should motivate further research in the field of metabolomics to identify the metabolic pathways driving the enhancement of MDSCs in order to effectively target their ability to promote tumour development and progression.
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Affiliation(s)
- Cong Hu
- Central Laboratory, The First Hospital of Jilin University, 130031, Changchun, Jilin, China
- Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, 130021, Changchun, Jilin, China
- Center for Reproductive Medicine, Center for Prenatal Diagnosis, The First Hospital of Jilin University, 130021, Changchun, Jilin, China
| | - Bo Pang
- Central Laboratory, The First Hospital of Jilin University, 130031, Changchun, Jilin, China
- Department of Cardiology, The First Hospital of Jilin University, 130031, Changchun, Jilin, China
| | - Guangzhu Lin
- Department of Cardiology, The First Hospital of Jilin University, 130031, Changchun, Jilin, China
| | - Yu Zhen
- Department of Dermatology, The First Hospital of Jilin University, 130021, Changchun, Jilin, China
| | - Huanfa Yi
- Central Laboratory, The First Hospital of Jilin University, 130031, Changchun, Jilin, China.
- Key Laboratory of Organ Regeneration and Transplantation, Ministry of Education, 130021, Changchun, Jilin, China.
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41
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Horman S, Dechamps M, Octave M, Lepropre S, Bertrand L, Beauloye C. Platelet Function and Coronary Microvascular Dysfunction. Microcirculation 2020. [DOI: 10.1007/978-3-030-28199-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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42
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Roles of Achieved Levels of Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein on Cardiovascular Outcome in Statin Therapy. Cardiovasc Ther 2019; 2019:3824823. [PMID: 31885691 PMCID: PMC6906885 DOI: 10.1155/2019/3824823] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/16/2019] [Accepted: 08/29/2019] [Indexed: 12/13/2022] Open
Abstract
In statin therapy, the prognostic role of achieved low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) in cardiovascular outcomes has not been fully elucidated. A total of 4,803 percutaneous coronary intervention (PCI)-naïve patients who prescribed moderate intensity of statin therapy were followed up. Total and each component of major adverse cardiovascular events (MACE) according to LDL-C and hsCRP quartiles were compared. The incidence of 5-year total MACEs in the highest quartile group according to the followed-up hsCRP was higher than that in the lowest quartile (hazard ratio (HR) = 2.16, p < 0.001). However, there was no difference between the highest and lowest quartiles of the achieved LDL-C (HR = 0.95, p = 0.743). After adjustment of potential confounders, the incidence of total death, de novo PCI, atrial fibrillation, and heart failure in the highest quartile of followed-up hsCRP, was higher than that in the lowest quartile (all p < 0.05). However, other components except for de novo PCI in the highest quartile by achieved LDL-C was not different to that in the lowest quartile. These results suggest that followed-up hsCRP can be more useful for predicting future cardiovascular outcome than achieved LDL-C in PCI-naïve patients with statin therapy.
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43
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Pernes G, Flynn MC, Lancaster GI, Murphy AJ. Fat for fuel: lipid metabolism in haematopoiesis. Clin Transl Immunology 2019; 8:e1098. [PMID: 31890207 PMCID: PMC6928762 DOI: 10.1002/cti2.1098] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 12/02/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
The importance of metabolic regulation in the immune system has launched back into the limelight in recent years. Various metabolic pathways have been examined in the context of their contribution to maintaining immune cell homeostasis and function. Moreover, this regulation is also important in the immune cell precursors, where metabolism controls their maintenance and cell fate. This review will discuss lipid metabolism in the context of haematopoiesis, that is blood cell development. We specifically focus on nonoxidative lipid metabolism which encapsulates the synthesis and degradation of the major lipid classes such as phospholipids, sphingolipids and sterols. We will also discuss how these metabolic processes are affected by haematological malignancies such as leukaemia and lymphoma, which are known to have altered metabolism, and how these different pathways contribute to the pathology.
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Affiliation(s)
- Gerard Pernes
- Haematopoiesis and Leukocyte Biology Baker Heart and Diabetes Institute Melbourne VIC Australia.,Department of Immunology Monash University Melbourne VIC Australia
| | - Michelle C Flynn
- Haematopoiesis and Leukocyte Biology Baker Heart and Diabetes Institute Melbourne VIC Australia.,Department of Immunology Monash University Melbourne VIC Australia
| | - Graeme I Lancaster
- Haematopoiesis and Leukocyte Biology Baker Heart and Diabetes Institute Melbourne VIC Australia.,Department of Immunology Monash University Melbourne VIC Australia
| | - Andrew J Murphy
- Haematopoiesis and Leukocyte Biology Baker Heart and Diabetes Institute Melbourne VIC Australia.,Department of Immunology Monash University Melbourne VIC Australia
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44
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Abstract
PURPOSE OF REVIEW Monocytes and macrophages are key players in the pathogenesis of atherosclerosis and dictate atherogenesis growth and stability. The heterogeneous nature of myeloid cells concerning their metabolic and phenotypic function is increasingly appreciated. This review summarizes the recent monocyte and macrophage literature and highlights how differing subsets contribute to atherogenesis. RECENT FINDINGS Monocytes are short-lived cells generated in the bone marrow and released to circulation where they can produce inflammatory cytokines and, importantly, differentiate into long-lived macrophages. In the context of cardiovascular disease, a myriad of subtypes, exist with each differentially contributing to plaque development. Herein we describe recent novel characterizations of monocyte and macrophage subtypes and summarize the recent literature on mediators of myelopoiesis. SUMMARY An increased understanding of monocyte and macrophage phenotype and their molecular regulators is likely to translate to the development of new therapeutic targets to either stem the growth of existing plaques or promote plaque stabilization.
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Affiliation(s)
- Jaume Amengual
- Division of Nutritional Sciences, Department of Food Sciences and Human Nutrition, University of Illinois Urbana Champaign, Urbana, Illinois
| | - Tessa J. Barrett
- Division of Cardiology, Department of Medicine, New York University, New York, New York, USA
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45
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Mushenkova NV, Summerhill VI, Silaeva YY, Deykin AV, Orekhov AN. Modelling of atherosclerosis in genetically modified animals. Am J Transl Res 2019; 11:4614-4633. [PMID: 31497187 PMCID: PMC6731422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/15/2019] [Indexed: 06/10/2023]
Abstract
Atherosclerosis is a lipid-driven, chronic inflammatory disease that leads to plaque formation at specific sites of the arterial tree. Being the common cause of many cardiovascular disorders, atherosclerosis makes a tremendous impact on morbidity and mortality rates of cardiovascular diseases (CVDs) in countries with higher income. Animal models of atherosclerosis are utilized as useful tools for studying the aetiology, pathogenesis and complications of atherosclerosis, thus, providing a valuable platform for the efficacy testing of different pharmacological therapies and validation of imaging techniques. To date, a large variety of models is available. Pathophysiological changes can be induced in animals by either an atherogenic diet or genetic manipulations. The discussion of advantages and disadvantages of some murine, rabbit and porcine genetic models currently available for the atherosclerosis research is the scope of the following review.
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Affiliation(s)
| | - Volha I Summerhill
- Institute for Atherosclerosis Research, Skolkovo Innovative CentreMoscow 121609, Russia
| | - Yulia Yu Silaeva
- Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences34/5 Vavilova Street, Moscow 119334, Russia
| | - Alexey V Deykin
- Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences34/5 Vavilova Street, Moscow 119334, Russia
| | - Alexander N Orekhov
- Institute for Atherosclerosis Research, Skolkovo Innovative CentreMoscow 121609, Russia
- Centre of Collective Usage, Institute of Gene Biology, Russian Academy of Sciences34/5 Vavilova Street, Moscow 119334, Russia
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46
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Kanter JE, Shao B, Kramer F, Barnhart S, Shimizu-Albergine M, Vaisar T, Graham MJ, Crooke RM, Manuel CR, Haeusler RA, Mar D, Bomsztyk K, Hokanson JE, Kinney GL, Snell-Bergeon JK, Heinecke JW, Bornfeldt KE. Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes. J Clin Invest 2019; 129:4165-4179. [PMID: 31295146 DOI: 10.1172/jci127308] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) increases the risk of atherosclerotic cardiovascular disease (CVD) in humans by poorly understood mechanisms. Using mouse models of T1DM-accelerated atherosclerosis, we found that relative insulin deficiency rather than hyperglycemia elevated levels of apolipoprotein C3 (APOC3), an apolipoprotein that prevents clearance of triglyceride-rich lipoproteins (TRLs) and their remnants. We then showed that serum APOC3 levels predict incident CVD events in subjects with T1DM in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. To explore underlying mechanisms, we investigated the impact of Apoc3 antisense oligonucleotides (ASOs) on lipoprotein metabolism and atherosclerosis in a mouse model of T1DM. Apoc3 ASO treatment abolished the increased hepatic Apoc3 expression in diabetic mice - resulting in lower levels of TRLs - without improving glycemic control. APOC3 suppression also prevented arterial accumulation of APOC3-containing lipoprotein particles, macrophage foam cell formation, and the accelerated atherosclerosis in diabetic mice. Our observations demonstrate that relative insulin deficiency increases APOC3 and that this results in elevated levels of TRLs and accelerated atherosclerosis in a mouse model of T1DM. Because serum levels of APOC3 predicted incident CVD events in the CACTI study, inhibiting APOC3 might reduce CVD risk in T1DM patients.
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Affiliation(s)
- Jenny E Kanter
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Baohai Shao
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Farah Kramer
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Shelley Barnhart
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Masami Shimizu-Albergine
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Tomas Vaisar
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | | | | | - Clarence R Manuel
- Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
| | - Rebecca A Haeusler
- Department of Pathology and Cell Biology, Columbia University, New York, New York, USA
| | - Daniel Mar
- Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, Washington, USA
| | - Karol Bomsztyk
- Department of Medicine, Division of Allergy and Infectious Disease, University of Washington, Seattle, Washington, USA
| | - John E Hokanson
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
| | - Gregory L Kinney
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, Colorado, USA
| | - Janet K Snell-Bergeon
- Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Denver, Aurora, Colorado, USA
| | - Jay W Heinecke
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA
| | - Karin E Bornfeldt
- Department of Medicine, UW Medicine Diabetes Institute, University of Washington, Seattle, Washington, USA.,Department of Pathology, University of Washington, Seattle, Washington, USA
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47
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Modulation of Bone and Marrow Niche by Cholesterol. Nutrients 2019; 11:nu11061394. [PMID: 31234305 PMCID: PMC6628005 DOI: 10.3390/nu11061394] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/14/2019] [Accepted: 06/17/2019] [Indexed: 12/21/2022] Open
Abstract
Bone is a complex tissue composing of mineralized bone, bone cells, hematopoietic cells, marrow adipocytes, and supportive stromal cells. The homeostasis of bone and marrow niche is dynamically regulated by nutrients. The positive correlation between cardiovascular disease and osteoporosis risk suggests a close relationship between hyperlipidemia and/or hypercholesterolemia and the bone metabolism. Cholesterol and its metabolites influence the bone homeostasis through modulating the differentiation and activation of osteoblasts and osteoclasts. The effects of cholesterol on hematopoietic stem cells, including proliferation, migration, and differentiation, are also well-documented and further relate to atherosclerotic lesions. Correlation between circulating cholesterol and bone marrow adipocytes remains elusive, which seems opposite to its effects on osteoblasts. Epidemiological evidence has demonstrated that cholesterol deteriorates or benefits bone metabolism depending on the types, such as low-density lipoprotein (LDL) or high-density lipoprotein (HDL) cholesterol. In this review, we will summarize the latest progress of how cholesterol regulates bone metabolism and bone marrow microenvironment, including the hematopoiesis and marrow adiposity. Elucidation of these association and factors is of great importance in developing therapeutic options for bone related diseases under hypercholesterolemic conditions.
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48
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Abstract
PURPOSE OF REVIEW Metabolic reprogramming is increasingly recognized as an essential trait of functional activation of immune cells. Here, we describe the link between immuno-metabolism, diabetes, and diabetic nephropathy. RECENT FINDINGS Crosstalk between cellular metabolic functions and immune activation occurs when plasma levels of glucose, triglycerides, and free fatty acids increase, thus promoting systemic low-grade inflammation that further boosts the development of metabolic complications. In the long run, this settles an "apparent paradox," where, despite excessive inflammation, the immune system is suppressed, further promoting progression to end-stage renal disease (ESRD) and predisposing to premature deaths from infections and cardiovascular diseases. Reviewing the effects of diabetes treatments on immuno-inflammatory responses suggests that the benefit of these drugs might extend beyond the simple control of glucose homeostasis. Hyperglycemia and dyslipidemia correlate with enhancement of the immuno-inflammatory response that can promote and worsen metabolic diseases and support the progression toward ESRD. The identification of cellular checkpoints that modulate the immuno-metabolic machinery of immune cells opens new venues for metabolic drugs.
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Affiliation(s)
- Fabrizia Bonacina
- Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
| | - Andrea Baragetti
- Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
- SISA Centre, Bassini Hospital, 20092, Cinisello Balsamo, Italy
| | - Alberico Luigi Catapano
- Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy
- IRCSS Multimedica, 20138, Milan, Italy
| | - Giuseppe Danilo Norata
- Department of Excellence of Pharmacological and Biomolecular Sciences (DisFeB), Università Degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
- SISA Centre, Bassini Hospital, 20092, Cinisello Balsamo, Italy.
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49
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Chipont A, Esposito B, Challier I, Montabord M, Tedgui A, Mallat Z, Loyer X, Potteaux S. MicroRNA-21 Deficiency Alters the Survival of Ly-6C
lo
Monocytes in
ApoE
−/−
Mice and Reduces Early-Stage Atherosclerosis—Brief Report. Arterioscler Thromb Vasc Biol 2019; 39:170-177. [DOI: 10.1161/atvbaha.118.311942] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Objective—
To determine the role of microRNA-21 (miR-21) on the homeostasis of monocyte subsets and on atherosclerosis development in
ApoE
−/−
(apolipoprotein E) mice.
Approach and Results—
In
ApoE
−/−
mice, miR-21 expression was increased in circulating Ly-6C
lo
nonclassical monocytes in comparison to Ly-6C
hi
monocytes. The absence of miR-21 significantly altered the survival and number of circulating Ly-6C
lo
nonclassical monocytes in
ApoE
−/−
mice. In the early stages of atherosclerosis, the absence of miR-21 limited lesion development both in the aortic sinus (by almost 30%) and in the aorta (by almost 50%). This was associated with less monocyte availability in circulation and increased apoptosis of local macrophages in plaques. At later stages of atherosclerosis, lesion size in the aortic root was similar in
ApoE
−/−
and
ApoE
−/−
miR-21
−/−
mice, but plaques showed a less stable phenotype (larger necrotic cores) in the latter. The loss of protection in advanced stages was most likely because of excessive inflammatory apoptosis related to an impairment of local efficient efferocytosis.
Conclusions—
Gene deletion of miR-21 in
ApoE
−/−
mice alters Ly-6C
lo
nonclassical monocytes homeostasis and contribute to limit early-stage atherosclerosis.
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Affiliation(s)
- Anna Chipont
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Bruno Esposito
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Inès Challier
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Mélanie Montabord
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Alain Tedgui
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Ziad Mallat
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Xavier Loyer
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
| | - Stephane Potteaux
- From the Inserm U970, Paris Cardiovascular Research Center (PARCC), Université René Descartes Paris 5, France
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50
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Etwebi Z, Landesberg G, Preston K, Eguchi S, Scalia R. Mechanistic Role of the Calcium-Dependent Protease Calpain in the Endothelial Dysfunction Induced by MPO (Myeloperoxidase). Hypertension 2019; 71:761-770. [PMID: 29507101 DOI: 10.1161/hypertensionaha.117.10305] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Revised: 10/02/2017] [Accepted: 01/12/2018] [Indexed: 01/07/2023]
Abstract
MPO (myeloperoxidase) is a peroxidase enzyme secreted by activated leukocytes that plays a pathogenic role in cardiovascular disease, mainly by initiating endothelial dysfunction. The molecular mechanisms of the endothelial damaging action of MPO remain though largely elusive. Calpain is a calcium-dependent protease expressed in the vascular wall. Activation of calpains has been implicated in inflammatory disorders of the vasculature. Using endothelial cells and genetically modified mice, this study identifies the µ-calpain isoform as novel downstream signaling target of MPO in endothelial dysfunction. Mouse lung microvascular endothelial cells were stimulated with 10 nmol/L MPO for 180 minutes. MPO denitrosylated µ-calpain C-terminus domain, and time dependently activated µ-calpain, but not the m-calpain isoform. MPO also reduced Thr172 AMPK (AMP-activated protein kinase) and Ser1177 eNOS (endothelial nitric oxide synthase) phosphorylation via upregulation of PP2A (protein phosphatase 2) expression. At the functional level, MPO increased endothelial VCAM-1 (vascular cell adhesion molecule 1) abundance and the adhesion of leukocytes to the mouse aorta. In MPO-treated endothelial cells, pharmacological inhibition of calpain activity attenuated expression of VCAM-1 and PP2A, and restored Thr172 AMPK and Ser1177 eNOS phosphorylation. Compared with wild-type mice, µ-calpain deficient mice experienced reduced leukocyte adhesion to the aortic endothelium in response to MPO. Our data first establish a role for calpain in the endothelial dysfunction and vascular inflammation of MPO. The MPO/calpain/PP2A signaling pathway may provide novel pharmacological targets for the treatment of inflammatory vascular disorders.
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Affiliation(s)
- Zienab Etwebi
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Gavin Landesberg
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Kyle Preston
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Satoru Eguchi
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA
| | - Rosario Scalia
- From the Department of Physiology and the Cardiovascular Research Center, Temple University, Philadelphia, PA.
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