TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction
Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial driver of cardiac fibrosis, leading to extensive extracellular matrix (ECM) deposition that increases myocardial stiffness and eventually impairs heart function. Mechanotransduction has merged as a key regulator of CF activatio...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Cell Insight |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772892725000306 |
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| author | Jie Liu Jingjing Feng Jingxuan Zhao Xiangjie Kong Zhangyi Yu Yuanru Huang Zechun He Mengxin Liu Zheng Liu Zhibing Lu Li Wang |
| author_facet | Jie Liu Jingjing Feng Jingxuan Zhao Xiangjie Kong Zhangyi Yu Yuanru Huang Zechun He Mengxin Liu Zheng Liu Zhibing Lu Li Wang |
| author_sort | Jie Liu |
| collection | DOAJ |
| description | Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial driver of cardiac fibrosis, leading to extensive extracellular matrix (ECM) deposition that increases myocardial stiffness and eventually impairs heart function. Mechanotransduction has merged as a key regulator of CF activation and the fibrotic response post-myocardial infarction (MI). However, the molecular mechanisms linking CF activation to mechanical cues within the injured myocardium remain poorly understood. Here we identified transcription factor TFAP4 as a central regulator of fibrosis in both human and murine models. TFAP4 overexpression enhances CF proliferation, ECM protein expression, and myofibroblast differentiation. Notably, TFAP4 directly activates expression of mechanosensors including Itga11 and Piezo2, which are essential for transmitting mechanical signals that promote CF activation and fibrosis. Silencing Itga11 and Piezo2 reverses the pro-fibrotic effects of TFAP4, while TFAP4 downregulation in vivo reduces fibrosis and improves cardiac function post-MI. These findings identify TFAP4 as a pivotal link between mechanotransduction and fibrosis, suggesting it as a potential therapeutic target to mitigate fibrosis and enhance cardiac recovery following MI. |
| format | Article |
| id | doaj-art-9e91daf1bf9c403c9fd9abc69bc0160b |
| institution | Kabale University |
| issn | 2772-8927 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Insight |
| spelling | doaj-art-9e91daf1bf9c403c9fd9abc69bc0160b2025-08-20T03:33:06ZengElsevierCell Insight2772-89272025-08-014410025610.1016/j.cellin.2025.100256TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransductionJie Liu0Jingjing Feng1Jingxuan Zhao2Xiangjie Kong3Zhangyi Yu4Yuanru Huang5Zechun He6Mengxin Liu7Zheng Liu8Zhibing Lu9Li Wang10Department of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, ChinaThe Institute for Advanced Studies, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei , ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, China; Hubei Provincial Clinical Research Center for Cardiovascular Intervention, Wuhan 430071, Hubei, ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, ChinaThe Institute for Advanced Studies, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei , ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, China; Hubei Provincial Clinical Research Center for Cardiovascular Intervention, Wuhan 430071, Hubei, ChinaDepartment of Cardiology, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, Hubei, China; Institute of Myocardial Injury and Repair, Wuhan University, Wuhan 430071, Hubei, China; Corresponding author. Room 1324, 115 Donghu Road, Wuchang District, Wuhan 430071, Hubei, China.Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial driver of cardiac fibrosis, leading to extensive extracellular matrix (ECM) deposition that increases myocardial stiffness and eventually impairs heart function. Mechanotransduction has merged as a key regulator of CF activation and the fibrotic response post-myocardial infarction (MI). However, the molecular mechanisms linking CF activation to mechanical cues within the injured myocardium remain poorly understood. Here we identified transcription factor TFAP4 as a central regulator of fibrosis in both human and murine models. TFAP4 overexpression enhances CF proliferation, ECM protein expression, and myofibroblast differentiation. Notably, TFAP4 directly activates expression of mechanosensors including Itga11 and Piezo2, which are essential for transmitting mechanical signals that promote CF activation and fibrosis. Silencing Itga11 and Piezo2 reverses the pro-fibrotic effects of TFAP4, while TFAP4 downregulation in vivo reduces fibrosis and improves cardiac function post-MI. These findings identify TFAP4 as a pivotal link between mechanotransduction and fibrosis, suggesting it as a potential therapeutic target to mitigate fibrosis and enhance cardiac recovery following MI.http://www.sciencedirect.com/science/article/pii/S2772892725000306Cardiac fibrosisFibroblast activationMechanotransductionTFAP4 |
| spellingShingle | Jie Liu Jingjing Feng Jingxuan Zhao Xiangjie Kong Zhangyi Yu Yuanru Huang Zechun He Mengxin Liu Zheng Liu Zhibing Lu Li Wang TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction Cell Insight Cardiac fibrosis Fibroblast activation Mechanotransduction TFAP4 |
| title | TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction |
| title_full | TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction |
| title_fullStr | TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction |
| title_full_unstemmed | TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction |
| title_short | TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction |
| title_sort | tfap4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction |
| topic | Cardiac fibrosis Fibroblast activation Mechanotransduction TFAP4 |
| url | http://www.sciencedirect.com/science/article/pii/S2772892725000306 |
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