MRTF-A-AOC3轴调控肌成纤维细胞激活促进心肌纤维化的机制研究

心肌纤维化过程中心脏固有成纤维细胞可以转分化为肌成纤维细胞。这一病理生理学过程在多种心脏病发展进程中发挥关键作用，但肌成纤维细胞具体作用机制尚未阐明。我们的预实验结果表明转录辅因子MRTF-A在肌成纤维细胞激活过程中表达水平及核定位均上调。肌成纤维细胞特异敲除MRTF-A小鼠在心梗模型中发生心肌纤维化程度明显减轻。RNA-seq分析提示，MRTF-A可能通过激活氨氧化酶AOC3转录驱动成纤维细胞向肌成纤维细胞转化进而促进心肌纤维化。本项目拟在此基础上利用肌成纤维细胞敲除/过表达MRTF-A小鼠、肌成纤维细胞AOC3敲除小鼠、AOC3小分子抑制剂等手段系统阐述MRTF-A-AOC3轴线促进肌成纤维细胞激活及心肌纤维化的作用机制，为探索心肌纤维化及心衰治疗提供新的理论依据。

Trans-differentiation of cardiac resident fibroblast into mature myofibroblast represents a hallmark event in cardiac fibrosis playing key roles in the occurrence and development of a wide range of chronic heart diseases including heart failure. The regulatory mechanism underlying this process remains incompletely understood. Our preliminary data show that myocardin-related transcription factor A (MRTF-A) is up-regulated in both expression levels and nuclear enrichment during fibroblast-myofibroblast transition. In addition, myofibroblast-specific deletion of MRTF-A suffices to attenuate cardiac fibrosis in mice following myocardial infarction. RNA-seq analysis indicates that MRTF-A directly activates the transcription of amine oxidase 3 (AOC3) in fibroblasts, which in turn drives myofibroblast activation. Based on these observations, we hypothesize that an MRTF-A-AOC3 axis may mediate fibroblast-myofibroblast transition and contribute to cardiac fibrosis. We propose to investigate this scheme using myofibroblast conditional MRTF-A knockout/knock-in mice, myofibroblast conditional AOC3 knockout mice, and small-molecule AOC3 inhibitors. We aim to elucidate the mechanism whereby this MRTF-A-AOC3 axis regulates fibroblast-myofibroblast transition and cardiac fibrosis. Our long-term goal is to provide a strong rationale for targeting this MRTF-A-AOC3 axis as a therapeutic approach in the intervention of cardiac fibrosis and heart failure.