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<p>Excessive fibrogenesis is associated with adverse cardiac remodeling and heart failure. Myofibroblast, primarily derived resident fibroblast, is the effector cell type in cardiac fibrosis. The mechanism whereby fibroblast–myofibroblast transition is driven remains incompletely understood. In the present study, we investigated the role and targetability of vascular adhesion protein 1 (VAP1) in cardiac fibrosis. Transcriptomic screening identified VAP1 as a direct target for megakaryocytic leukemia 1 (MKL1), a master regulator of tissue fibrosis. VAP1 silencing in primary cardiac fibroblasts down-regulated expression of myofibroblast markers and weakened cell proliferation/migration/contraction when exposed to transforming growth factor-β, whereas VAP1 over-expression exerted the opposite effects. Importantly, VAP1 deletion in quiescent fibroblasts or activated fibroblasts (myofibroblasts), achieved through the <i>Col1a2</i>-Cre driver and the <i>Postn</i>-Cre driver, respectively, dampened cardiac fibrosis and rescued heart function in mice subjected to the transverse aortic constriction procedure. Data obtained from multi-omics techniques indicated that VAP1 influenced fibroblast–myofibroblast transition by directly interacting with platelet-derived growth factor receptor-beta to enable signal transduction. Finally, small-molecule VAP1 inhibitors attenuated cardiac fibrosis and improved heart function in mice. In conclusion, our data support a role for VAP1 in driving fibroblast activation and cardiac fibrosis. Therefore, targeting VAP1 can be considered as a reasonable approach for the intervention of heart failure.</p>

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VAP1 promotes cardiac fibrosis by enabling PDGFR signaling in myofibroblasts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Shan Huang,
  • Qianwen Zhao,
  • Tinghui Shao,
  • Chenghao Zhu,
  • Yujia Xue,
  • Naxia Chen,
  • Yue Zhang,
  • Huihui Xu,
  • Ming Kong,
  • Rui Wang

摘要

Excessive fibrogenesis is associated with adverse cardiac remodeling and heart failure. Myofibroblast, primarily derived resident fibroblast, is the effector cell type in cardiac fibrosis. The mechanism whereby fibroblast–myofibroblast transition is driven remains incompletely understood. In the present study, we investigated the role and targetability of vascular adhesion protein 1 (VAP1) in cardiac fibrosis. Transcriptomic screening identified VAP1 as a direct target for megakaryocytic leukemia 1 (MKL1), a master regulator of tissue fibrosis. VAP1 silencing in primary cardiac fibroblasts down-regulated expression of myofibroblast markers and weakened cell proliferation/migration/contraction when exposed to transforming growth factor-β, whereas VAP1 over-expression exerted the opposite effects. Importantly, VAP1 deletion in quiescent fibroblasts or activated fibroblasts (myofibroblasts), achieved through the Col1a2-Cre driver and the Postn-Cre driver, respectively, dampened cardiac fibrosis and rescued heart function in mice subjected to the transverse aortic constriction procedure. Data obtained from multi-omics techniques indicated that VAP1 influenced fibroblast–myofibroblast transition by directly interacting with platelet-derived growth factor receptor-beta to enable signal transduction. Finally, small-molecule VAP1 inhibitors attenuated cardiac fibrosis and improved heart function in mice. In conclusion, our data support a role for VAP1 in driving fibroblast activation and cardiac fibrosis. Therefore, targeting VAP1 can be considered as a reasonable approach for the intervention of heart failure.