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Rao W, Li D, Zhang Q, Liu T, Gu Z, Huang L, Dai J, Wang J, Hou X. Complex regulation of cardiac fibrosis: insights from immune cells and signaling pathways. J Transl Med 2025; 23:242. [PMID: 40022104 PMCID: PMC11869728 DOI: 10.1186/s12967-025-06260-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/16/2025] [Indexed: 03/03/2025] Open
Abstract
Cardiac fibrosis is a physiological process that involves the formation of scar tissue in the heart in response to injury or damage. This process is initially a protective measure characterized by enhanced fibroblasts, which are responsible for producing extracellular matrix proteins that provide structural support to the heart. However, when fibrosis becomes excessive, it can lead to adverse outcomes, including increasing tissue stiffness and impaired cardiac function, which can ultimately result in heart failure with a poor prognosis. While fibroblasts are the primary cells involved in cardiac fibrosis, immune cells have also been found to play a vital role in its progression. Recent research has shown that immune cells exert multifaceted effects besides regulation of inflammatory response. Advanced research techniques such as single-cell sequencing and multiomics have provided insights into the specific subsets of immune cells involved in fibrosis and the complex regulation of the process. Targeted immunotherapy against fibrosis is gaining traction as a potential treatment option, but it is still unclear how immune cells achieve this regulation and whether distinct subsets are involved in different roles. To better understand the role of immune cells in cardiac fibrosis, it is essential to examine the classical signaling pathways that are closely related to fibrosis formation. We have also focused on the unique properties of diverse immune cells in cardiac fibrosis and their specific intercommunications. Therefore, this review will delve into the plasticity and heterogeneity of immune cells and their specific roles in cardiac fibrosis, which propose insights to facilitate the development of anti-fibrosis therapeutic strategies.
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Affiliation(s)
- Wutian Rao
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Li
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinghang Zhang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Tianbao Liu
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhengying Gu
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lin Huang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinjie Dai
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayi Wang
- Department of Clinical Laboratory Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xumin Hou
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Hospital's Office, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Guo S, Zhang Q, Guo Y, Yin X, Zhang P, Mao T, Tian Z, Li X. The role and therapeutic targeting of the CCL2/CCR2 signaling axis in inflammatory and fibrotic diseases. Front Immunol 2025; 15:1497026. [PMID: 39850880 PMCID: PMC11754255 DOI: 10.3389/fimmu.2024.1497026] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/11/2024] [Indexed: 01/25/2025] Open
Abstract
CCL2, a pivotal cytokine within the chemokine family, functions by binding to its receptor CCR2. The CCL2/CCR2 signaling pathway plays a crucial role in the development of fibrosis across multiple organ systems by modulating the recruitment and activation of immune cells, which in turn influences the progression of fibrotic diseases in the liver, intestines, pancreas, heart, lungs, kidneys, and other organs. This paper introduces the biological functions of CCL2 and CCR2, highlighting their similarities and differences concerning fibrotic disorders in various organ systems, and reviews recent progress in the diagnosis and treatment of clinical fibrotic diseases linked to the CCL2/CCR2 signaling pathway. Additionally, further in-depth research is needed to explore the clinical significance of the CCL2/CCR2 axis in fibrotic conditions affecting different organs.
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Affiliation(s)
| | | | | | | | | | | | | | - Xiaoyu Li
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Bogert NV, Therre M, Din S, Furkel J, Zhou X, El-Battrawy I, Heineke J, Schweizer PA, Akin I, Katus HA, Frey N, Leuschner F, Konstandin MH. Macrophages enhance sodium channel expression in cardiomyocytes. Basic Res Cardiol 2024; 119:1063-1073. [PMID: 39382673 PMCID: PMC11628573 DOI: 10.1007/s00395-024-01084-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 09/22/2024] [Accepted: 09/29/2024] [Indexed: 10/10/2024]
Abstract
Cardiac macrophages facilitate electrical conduction through the atrioventricular-node (AV) in mice. A possible role for cardiomyocyte-macrophage coupling on the effect of antiarrhythmic therapy has not been investigated yet. Holter monitoring was conducted in LysMCrexCsf1rLsL-DTR mice (MMDTR) under baseline conditions and after an elctrophysiological stress test by flecainide. In vivo effects were recapitulated in vitro by patch-clamp experiments. The underlying mechanism was characterized by expression and localization analysis of connexin43 (Cx43) and voltage-gated-sodium-channel-5 (Nav1.5). ECG monitoring in MMDTR mice did not show any significant conduction abnormalities but a significantly attenuated flecainide-induced extension of RR- and PP-intervals. Patch-clamp analysis revealed that the application of flecainide to neonatal rat ventricular cardiomyocytes (CMs) changed their resting-membrane-potential (RMP) to more negative potentials and decreased action-potential-duration (APD50). Coupling of macrophages to CMs significantly enhances the effects of flecainide, with a further reduction of the RMP and APD50, mediated by an upregulation of Cx43 and Nav1.5 surface expression. Macrophage depletion in mice does not correlate with cardiac electric conduction delay. Cardiac macrophages amplify the effects of flecainide on electrophysiological properties of cardiomyocytes in vivo and in vitro. Mechanistically, formation of macrophage-cardiomyocyte cell-cell-contacts via Cx43 facilitates the recruitment of Nav1.5 to the cell membrane increasing flecainide effects.
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Affiliation(s)
- N V Bogert
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - M Therre
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - S Din
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - J Furkel
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - X Zhou
- Department of Cardiology, University Medical Centre Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - I El-Battrawy
- Department of Cardiology, BG Universitätsklinikum Bergmannsheil Bochum, Ruhr-University, Bochum, Germany
- Institut Für Forschung Und Lehre (IFL), Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - J Heineke
- Department of Cardiovascular Physiology, European Center for Angioscience, Medical Faculty Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - P A Schweizer
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - I Akin
- Department of Cardiology, University Medical Centre Mannheim, Ruprecht-Karls-University Heidelberg, Mannheim, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - H A Katus
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - N Frey
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - F Leuschner
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany
| | - M H Konstandin
- Department of Cardiology, University Hospital Heidelberg, Ruprecht-Karls-University Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg, Mannheim, Germany.
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Wang Z, Wang BH, Yang XL, Xia YL, Zhang SM, Che Y. Relationship of inflammatory indices with left atrial appendage thrombus or spontaneous echo contrast in patients with atrial fibrillation. World J Clin Cases 2024; 12:4550-4557. [PMID: 39070837 PMCID: PMC11235501 DOI: 10.12998/wjcc.v12.i21.4550] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Revised: 05/13/2024] [Accepted: 05/28/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Inflammatory indices derived from complete blood tests have been reported to be associated with poor outcomes in patients with atrial fibrillation (AF). The data about the relationship between inflammatory indices and left atrial appendage thrombus (LAAT) or dense spontaneous echo contrast (SEC) are limited. AIM To explore the value of inflammatory indices for predicting the presence of LAAT or dense SEC in nonvalvular AF patients. METHODS A total of 406 patients with nonvalvular AF who underwent transesophageal echocardiography were included and divided into two groups based on the presence (study group) or absence (control group) of LAAT or dense SEC. Inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), were calculated from complete blood analysis. The associations of inflammatory indices with LAAT/dense SEC were analyzed using logistic regression. RESULTS LAAT and dense SEC were detected in 11 (2.7%) and 42 (10.3%) patients, respectively. The PLR only showed an association with LAAT/dense SEC in the univariate model. Elevated NLR (odds ratio [OR] = 1.48, 95% confidence interval [CI]: 1.11-1.98, P = 0.007) and reduced LMR (OR = 0.59, 95%CI: 0.41-0.83, P = 0.003) were found to be independent risk factors for the presence of LAAT/dense SEC. The areas under the NLR and LMR curves for predicting LAAT/dense SEC were 0.73 (95%CI: 0.66-0.80, P < 0.001) and 0.73 (95%CI: 0.65-0.81, P < 0.001), respectively, while the cutoff values were 2.8 (sensitivity: 69.8%; specificity: 64.0%) and 2.4 (sensitivity: 71.7%; specificity: 60.6%), respectively. CONCLUSION Increased NLR and decreased LMR may predict LAAT/dense SEC in patients with nonvalvular AF.
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Affiliation(s)
- Zhao Wang
- Department of Ultrasonography, First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Bin-Hao Wang
- Arrhythmia Center, First Affiliated Hospital of Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Xiao-Lei Yang
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Yun-Long Xia
- Department of Cardiology, First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
| | - Sheng-Min Zhang
- Department of Ultrasonography, First Affiliated Hospital of Ningbo University, Ningbo 315000, Zhejiang Province, China
| | - Ying Che
- Department of Ultrasonography, First Affiliated Hospital of Dalian Medical University, Dalian 116000, Liaoning Province, China
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Yang B, Qiao Y, Yan D, Meng Q. Targeting Interactions between Fibroblasts and Macrophages to Treat Cardiac Fibrosis. Cells 2024; 13:764. [PMID: 38727300 PMCID: PMC11082988 DOI: 10.3390/cells13090764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 02/29/2024] [Accepted: 03/01/2024] [Indexed: 05/13/2024] Open
Abstract
Excessive extracellular matrix (ECM) deposition is a defining feature of cardiac fibrosis. Most notably, it is characterized by a significant change in the concentration and volume fraction of collagen I, a disproportionate deposition of collagen subtypes, and a disturbed ECM network arrangement, which directly affect the systolic and diastolic functions of the heart. Immune cells that reside within or infiltrate the myocardium, including macrophages, play important roles in fibroblast activation and consequent ECM remodeling. Through both direct and indirect connections to fibroblasts, monocyte-derived macrophages and resident cardiac macrophages play complex, bidirectional, regulatory roles in cardiac fibrosis. In this review, we discuss emerging interactions between fibroblasts and macrophages in physiology and pathologic conditions, providing insights for future research aimed at targeting macrophages to combat cardiac fibrosis.
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Affiliation(s)
- Bo Yang
- Center for Organoid and Regeneration Medicine, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Guangzhou 511466, China;
| | - Yan Qiao
- State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, School of Life Sciences, Inner Mongolia University, Hohhot 010021, China;
| | - Dong Yan
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China;
| | - Qinghang Meng
- Center for Organoid and Regeneration Medicine, Greater Bay Area Institute of Precision Medicine (Guangzhou), School of Life Sciences, Fudan University, Guangzhou 511466, China;
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Jayabalan M, Sankar S, Govindan M, Nagarathnam R, Ibrahim M. Effect of aqueous extract of Indigofera tinctoria ( Linn) on aging-induced inflammation and its associated left ventricular hypertrophy and fibrosis in the rat. 3 Biotech 2023; 13:407. [PMID: 37987026 PMCID: PMC10657343 DOI: 10.1007/s13205-023-03815-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Accepted: 10/15/2023] [Indexed: 11/22/2023] Open
Abstract
The aim of the present study is to investigate the ameliorative potential of the aqueous extract of Indigofera tinctoria (IT) in aging-induced inflammation and its associated cardiac hypertrophy and fibrosis. Young (3-month-old) and aged (24-26-month-old) male Wistar albino rats were grouped into young control, aged control, aged + IT, and young + IT. The animals in the supplementary groups received 200 mg/kg BWT of aqueous extract of IT orally once a day for 21 days. Aged animals showed prolonged QT interval and increased weight and volume of the heart with a thickening ventricular wall. Infiltration of leukocytes and increased cardiomyocyte diameter and decreased numerical density along with cardiomyocyte apoptosis and increased collagen accumulation were also seen in aged myocardium when compared to the young. The expression profile of various pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, NFκB, and iNOS was increased with a concomitant reduction in IL-10 expression in the aged compared to the young. In addition, a marked increase in ROS generation, TGF-β, and α-SMA levels is evident in the aged myocardium. These pathological changes were greatly reversed in aged animals supplemented with IT. Furthermore, the aged + IT group showed repression of pro-inflammatory markers with a subsequent increase in IL-10 expression. Contrarily, no marked changes were observed between young and young + IT groups. Taken together, it is concluded that the aqueous extract of Indigofera tinctoria suppresses cardiac fibrosis and hypertrophy by repressing the inflammation and its associated activation of TGFβ and myofibroblast conversion.
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Affiliation(s)
- Monisha Jayabalan
- Department of Anatomy, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600113 India
| | - Suruthi Sankar
- Department of Anatomy, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600113 India
| | - Muthukumar Govindan
- Unit of Plant Pathology, Center for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai, 600025 Tamil Nadu India
| | - Radhakrishnan Nagarathnam
- Unit of Plant Pathology, Center for Advanced Studies in Botany, University of Madras, Guindy Campus, Chennai, 600025 Tamil Nadu India
| | - Muhammed Ibrahim
- Department of Anatomy, Dr. ALM Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600113 India
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Nasab Mehrabi E, Toupchi‐Khosroshahi V, Athari SS. Relationship of atrial fibrillation and N terminal pro brain natriuretic peptide in heart failure patients. ESC Heart Fail 2023; 10:3250-3257. [PMID: 37776150 PMCID: PMC10682909 DOI: 10.1002/ehf2.14542] [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: 12/20/2022] [Revised: 07/15/2023] [Accepted: 09/15/2023] [Indexed: 10/01/2023] Open
Abstract
N terminal pro brain natriuretic peptide (NT-proBNP) plays an important role in the diagnosis and prognosis of heart failure (HF). The plasma level of NT-proBNP in atrial fibrillation (AF) patients was higher than of sinus rhythm patients. In HF, NT-proBNP levels are affected by the concomitant presence of AF, making it difficult to distinguish between HF and AF in patients with elevated NT-proBNP. Several other diseases, such as renal failure and pulmonary embolism, are known to further increase NT-proBNP levels in patients with concomitant HF. Therefore, NT-proBNP is a sensitive but non-specific marker for the detection of HF. AF is very important in this regard because among patients with HF regardless of ejection fraction, symptoms such as shortness of breath and atrial enlargement develop and can mimic HF. In the present study, we investigated whether the prognostic value of natriuretic peptides in HF holds true for patients with concomitant AF.
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Affiliation(s)
- Entezar Nasab Mehrabi
- Department of Cardiology, School of Medicine, Tehran Heart CenterTehran University of Medical SciencesTehranIran
- Department of Cardiology, School of MedicineValiasr Hospital, Zanjan University of Medical SciencesZanjanIran
| | - Vahid Toupchi‐Khosroshahi
- Department of Cardiology, School of MedicineValiasr Hospital, Zanjan University of Medical SciencesZanjanIran
- Department of Cardiology, School of MedicineAyatollah Mousavi Hospital, Zanjan University of Medical SciencesZanjanIran
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Sang W, Wang L, Yan X, Sun H, Han Y, Wang F, Tang B, Li Y. Establishment of Risk Model and Analysis of Immunoinfiltration Based on Mitophagy-Related Associated Genes in Atrial Fibrillation. J Inflamm Res 2023; 16:2561-2583. [PMID: 37346800 PMCID: PMC10281282 DOI: 10.2147/jir.s415410] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 06/13/2023] [Indexed: 06/23/2023] Open
Abstract
Objective Atrial fibrillation (AF) is a common tachyarrhythmia whose pathogenesis remains elusive. In the present study, we aimed to investigate the pathological mechanism of mitophagy and immunoinfiltration in AF. Methods First, we identified differentially expressed mitophagy-related genes (DEMRGs) based on the GSE79768 and GSE115574 datasets, subjecting them to functional enrichment analysis. STRING, TRRUST, miRNet, miRwalk, and Cytoscape were used to explore the potential regulatory roles of downstream signaling pathways. Subsequently, the random forest method was used to construct the AF risk model, and the DEMRGs most correlated with AF risk were determined by combining the Gini index. ssGSEA algorithm, NMF algorithm, and unsupervised clustering were used to subdivide AF molecular types. We then studied the characteristics of mitophagy- and immune infiltration-related genes in AF. Ultimately, we detected the expression of key genes in canine atrial tissues and HL-1 cells by immunofluorescence and Western blot. Results Mitophagy and immune infiltration were significantly enriched and activated in AF samples. Thirty-seven DEMRGs were screened, of which MAPK1, VDAC1, MAPK14, and MTERF3 were most associated with AF risk. The risk model based on these could identify patients at a high risk of AF. The infiltration of immunocells such as mast cells and neutrophils was significantly different among AF types. Finally, expression verification indicated that the expression trend of four key genes in canine atrial muscle tissue and HL-1 cells was consistent. Conclusion We found that mitophagy may participate in AF progression through immune activation. In addition, the AF risk prediction model composed of VDAC1, MAPK1, MAPK14, and MTERF3 has a good AF prediction performance, which provides new ideas for the study of AF pathogenesis and potential therapeutic targets.
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Affiliation(s)
- Wanyue Sang
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Lu Wang
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Xiaoji Yan
- Department of Emergency, Sir Run Run Shaw Hospital Affiliated to Zhejiang University School of Medicine, Hangzhou, Zhejiang, People’s Republic of China
| | - Huaxin Sun
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Yafan Han
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Feifei Wang
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Baopeng Tang
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
| | - Yaodong Li
- Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
- Xinjiang Key Laboratory of Cardiac Electrophysiology and Cardiac Remodeling, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China
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9
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Long non-coding RNA and circular RNA: new perspectives for molecular pathophysiology of atrial fibrillation. Mol Biol Rep 2023; 50:2835-2845. [PMID: 36596997 DOI: 10.1007/s11033-022-08216-0] [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: 07/12/2022] [Accepted: 12/15/2022] [Indexed: 01/05/2023]
Abstract
Many studies have demonstrated the association of atrial fibrillation (AF) with endogenous genetic regulatory mechanisms. These interactions could advance the understanding of the AF pathophysiological process, supporting the search for early biomarkers to improve diagnosis and disease monitoring. Among the endogenous genetic regulatory mechanisms, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have gained special attention, and studies have demonstrated their involvement in AF development and other AF-related diseases such as coronary artery disease and cardiomyopathy. This review describes the main experimental results reported by studies that analyzed the expression of lncRNAs and circRNAs in AF associated with miRNA or mRNA. The search was conducted in PubMed public database using the terms "lncRNA and atrial fibrillation" or "long ncRNA and atrial fibrillation" or "long non-coding RNA and atrial fibrillation" or "circular RNA and atrial fibrillation" or "circRNA and atrial fibrillation". There was no overlapping of lncRNA or circRNA among the studies, attributed to the different sample types, methods, species, and patient classification evaluated in these studies. Although the regulatory mechanisms in which these molecules are involved are not yet well understood, the studies analyzed show their importance in the pathophysiological process of AF, supporting the idea that lncRNAs and circRNAs are involved in miRNA or mRNA regulation in the molecular mechanism of this disease.
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Abstract
Histone proteins are a primary component of chromatin; therefore, any modifications to their structure are anticipated to affect the behavior of our genetic material, which is manifested in the form of phenotypic changes at a molecular, cellular or organic level. The majority of histone modifications are of either methylation or acetylation type that regulate gene expression. Though, not all of these modifications are concerned with the direct regulation of gene transcription. Throughout its 13-year run, Epigenomics has never ceased to cover these most gripping epigenetic stories, a significant proportion of which is in the matter of histones and their modifications. As such, the current perspective piece is intended to highlight original histone-oriented contributions published in Epigenomics since 2020.
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Affiliation(s)
- Milad Shirvaliloo
- Infectious & Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, 15731, Iran
- Future Science Group, Unitec House, 2 Albert Place, London, N3 1QB, UK
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11
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Yao Y, Yang M, Liu D, Zhao Q. Immune remodeling and atrial fibrillation. Front Physiol 2022; 13:927221. [PMID: 35936905 PMCID: PMC9355726 DOI: 10.3389/fphys.2022.927221] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
Atrial fibrillation (AF) is a highly prevalent arrhythmia that causes high morbidity and mortality. However, the underlying mechanism of AF has not been fully elucidated. Recent research has suggested that, during AF, the immune system changes considerably and interacts with the environment and cells involved in the initiation and maintenance of AF. This may provide a new direction for research and therapeutic strategies for AF. In this review, we elaborate the concept of immune remodeling based on available data in AF. Then, we highlight the complex relationships between immune remodeling and atrial electrical, structural and neural remodeling while also pointing out some research gaps in these field. Finally, we discuss several potential immunomodulatory treatments for AF. Although the heterogeneity of existing evidence makes it ambiguous to extrapolate immunomodulatory treatments for AF into the clinical practice, immune remodeling is still an evolving concept in AF pathophysiology and further studies within this field are likely to provide effective therapies for AF.
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Affiliation(s)
- Yajun Yao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Mei Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Dishiwen Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
| | - Qingyan Zhao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
- Cardiovascular Research Institute of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Cardiology, Wuhan, China
- *Correspondence: Qingyan Zhao,
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12
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Xia R, Tomsits P, Loy S, Zhang Z, Pauly V, Schüttler D, Clauss S. Cardiac Macrophages and Their Effects on Arrhythmogenesis. Front Physiol 2022; 13:900094. [PMID: 35812333 PMCID: PMC9257039 DOI: 10.3389/fphys.2022.900094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/30/2022] [Indexed: 12/24/2022] Open
Abstract
Cardiac electrophysiology is a complex system established by a plethora of inward and outward ion currents in cardiomyocytes generating and conducting electrical signals in the heart. However, not only cardiomyocytes but also other cell types can modulate the heart rhythm. Recently, cardiac macrophages were demonstrated as important players in both electrophysiology and arrhythmogenesis. Cardiac macrophages are a heterogeneous group of immune cells including resident macrophages derived from embryonic and fetal precursors and recruited macrophages derived from circulating monocytes from the bone marrow. Recent studies suggest antiarrhythmic as well as proarrhythmic effects of cardiac macrophages. The proposed mechanisms of how cardiac macrophages affect electrophysiology vary and include both direct and indirect interactions with other cardiac cells. In this review, we provide an overview of the different subsets of macrophages in the heart and their possible interactions with cardiomyocytes under both physiologic conditions and heart disease. Furthermore, we elucidate similarities and differences between human, murine and porcine cardiac macrophages, thus providing detailed information for researchers investigating cardiac macrophages in important animal species for electrophysiologic research. Finally, we discuss the pros and cons of mice and pigs to investigate the role of cardiac macrophages in arrhythmogenesis from a translational perspective.
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Affiliation(s)
- Ruibing Xia
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Philipp Tomsits
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Simone Loy
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Zhihao Zhang
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Valerie Pauly
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Dominik Schüttler
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
| | - Sebastian Clauss
- Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- Institute of Surgical Research at the Walter-Brendel-Centre of Experimental Medicine, University Hospital Munich, Ludwig-Maximilians-University Munich (LMU), Munich, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich, Munich Heart Alliance, Munich, Germany
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13
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S. Ramos K, Pool L, van Schie MS, Wijdeveld LFJM, van der Does WFB, Baks L, Sultan HMD, van Wijk SW, Bogers AJJC, Verheule S, de Groot NMS, Brundel BJJM. Degree of Fibrosis in Human Atrial Tissue Is Not the Hallmark Driving AF. Cells 2022; 11:cells11030427. [PMID: 35159236 PMCID: PMC8834228 DOI: 10.3390/cells11030427] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/11/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Background: The current paradigm is that fibrosis promotes electrophysiological disorders and drives atrial fibrillation (AF). In this current study, we investigated the relation between the degree of fibrosis in human atrial tissue samples of controls and patients in various stages of AF and the degree of electrophysiological abnormalities. Methods: The degree of fibrosis was measured in the atrial tissue and serum of patients in various stages of AF and the controls. Hereto, picrosirius and H&E staining were performed to quantify degree of total, endo-perimysial fibrosis, and cardiomyocyte diameter. Western blot quantified fibrosis markers: neural cell adhesion molecule, tissue inhibitor of metalloproteinase, lysyl oxidase, and α-smooth muscle actin. In serum, the ratio carboxyl-terminal telopeptide of collagen/matrix-metalloproteinase1 was determined. High-resolution epicardial mapping evaluated low-voltage areas and conduction abnormalities. Results: No significant differences were observed in the degree of fibrosis between the groups. Finally, no significant correlation—absolute nor spatial—was observed between all electrophysiological parameters and histological fibrosis markers. Conclusions: No differences in the degree of fibrosis were observed in patients from various stages of AF compared to the controls. Moreover, electrophysiological abnormalities did not correlate with any of the fibrosis markers. The findings indicate that fibrosis is not the hallmark of structural remodeling in AF.
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Affiliation(s)
- Kennedy S. Ramos
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
- Department Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; (M.S.v.S.); (W.F.B.v.d.D.); (N.M.S.d.G.)
- Correspondence: (K.S.R.); (B.J.J.M.B.)
| | - Lisa Pool
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
- Department Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; (M.S.v.S.); (W.F.B.v.d.D.); (N.M.S.d.G.)
| | - Mathijs S. van Schie
- Department Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; (M.S.v.S.); (W.F.B.v.d.D.); (N.M.S.d.G.)
| | - Leonoor F. J. M. Wijdeveld
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
| | - Willemijn F. B. van der Does
- Department Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; (M.S.v.S.); (W.F.B.v.d.D.); (N.M.S.d.G.)
| | - Luciënne Baks
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
| | - H. M. Danish Sultan
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
| | - Stan W. van Wijk
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
| | - Ad J. J. C. Bogers
- Department of Cardiothoracic Surgery, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands;
| | - Sander Verheule
- Department of Physiology, University Maastricht, 6211 LK Maastricht, The Netherlands;
| | - Natasja M. S. de Groot
- Department Cardiology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands; (M.S.v.S.); (W.F.B.v.d.D.); (N.M.S.d.G.)
| | - Bianca J. J. M. Brundel
- Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, 1081 HV Amsterdam, The Netherlands; (L.P.); (L.F.J.M.W.); (L.B.); (H.M.D.S.); (S.W.v.W.)
- Correspondence: (K.S.R.); (B.J.J.M.B.)
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14
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Legere SA, Haidl ID, Castonguay MC, Brunt KR, Légaré JF, Marshall JS. Increased mast cell density is associated with decreased fibrosis in human atrial tissue. J Mol Cell Cardiol 2020; 149:15-26. [PMID: 32931784 DOI: 10.1016/j.yjmcc.2020.09.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/29/2020] [Accepted: 09/02/2020] [Indexed: 12/31/2022]
Abstract
Fibrotic remodelling of the atria is poorly understood and can be regulated by myocardial immune cell populations after injury. Mast cells are resident immune sentinel cells present in the heart that respond to tissue damage and have been linked to fibrosis in other settings. The role of cardiac mast cells in fibrotic remodelling in response to human myocardial injury is controversial. In this study, we sought to determine the association between mast cells, atrial fibrosis, and outcomes in a heterogeneous population of cardiac surgical patients, including a substantial proportion of coronary artery bypass grafting patients. Atrial appendage from patients was assessed for collagen and mast cell density by histology and by droplet digital polymerase chain reaction (ddPCR) for mast cell associated transcripts. Clinical variables and outcomes were also followed. Mast cells were detected in human atrial tissue at varying densities. Histological and ddPCR assessment of mast cells in atrial tissue were closely correlated. Patients with high mast cell density had less fibrosis and lower severity of heart failure classification or incidence mortality than patients with low mast cell content. Analysis of a homogeneous population of coronary artery bypass graft patients yielded similar observations. Therefore, evidence from this study suggests that increased atrial mast cell populations are associated with decreased clinical cardiac fibrotic remodelling and improved outcomes, in cardiac surgery patients.
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Affiliation(s)
- Stephanie A Legere
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS, Canada; Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada; IMPART Investigator Team Canada, Canada
| | - Ian D Haidl
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS, Canada; Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada
| | - Mathieu C Castonguay
- Department of Pathology and Laboratory Medicine, QEII Health Sciences Centre, Halifax, NS, Canada
| | - Keith R Brunt
- Dalhousie Medicine New Brunswick, Department of Pharmacology, Saint John, NB, Canada; New Brunswick Heart Centre, Saint John, NB, Canada; IMPART Investigator Team Canada, Canada
| | - Jean-François Légaré
- Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada; Dalhousie Medicine New Brunswick, Department of Pharmacology, Saint John, NB, Canada; New Brunswick Heart Centre, Saint John, NB, Canada; IMPART Investigator Team Canada, Canada
| | - Jean S Marshall
- Dalhousie University, Department of Microbiology and Immunology, Halifax, NS, Canada; Dalhousie Human Immunology and Inflammation Group, Dalhousie University, Halifax, NS, Canada; IMPART Investigator Team Canada, Canada.
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15
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Okyere AD, Tilley DG. Leukocyte-Dependent Regulation of Cardiac Fibrosis. Front Physiol 2020; 11:301. [PMID: 32322219 PMCID: PMC7156539 DOI: 10.3389/fphys.2020.00301] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 03/17/2020] [Indexed: 12/24/2022] Open
Abstract
Cardiac fibrosis begins as an intrinsic response to injury or ageing that functions to preserve the tissue from further damage. Fibrosis results from activated cardiac myofibroblasts, which secrete extracellular matrix (ECM) proteins in an effort to replace damaged tissue; however, excessive ECM deposition leads to pathological fibrotic remodeling. At this extent, fibrosis gravely disturbs myocardial compliance, and ultimately leads to adverse outcomes like heart failure with heightened mortality. As such, understanding the complexity behind fibrotic remodeling has been a focal point of cardiac research in recent years. Resident cardiac fibroblasts and activated myofibroblasts have been proven integral to the fibrotic response; however, several findings point to additional cell types that may contribute to the development of pathological fibrosis. For one, leukocytes expand in number after injury and exhibit high plasticity, thus their distinct role(s) in cardiac fibrosis is an ongoing and controversial field of study. This review summarizes current findings, focusing on both direct and indirect leukocyte-mediated mechanisms of fibrosis, which may provide novel targeted strategies against fibrotic remodeling.
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Affiliation(s)
- Ama Dedo Okyere
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Douglas G Tilley
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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