心肌细胞分泌的Inhibin通过作用于心肌成纤维细胞调控心肌纤维化的机制研究

心肌纤维化出现在多种心脏疾病中，是引起心功能紊乱并导致心力衰竭的重要原因。本项目首次发现抑制素（Inhibin）在小鼠心肌纤维化时表达升高。心肌特异性敲除Inhibin加重了AngⅡ诱导的小鼠心肌纤维化。细胞实验发现，病理性刺激会诱导心肌细胞表达并分泌Inhibin，通过旁分泌作用抑制心肌成纤维细胞的激活。此外，Inhibin可以激活成纤维细胞内的Smad1/5信号、抑制Smad2/3信号，并且这些作用可能是通过细胞表面的Endoglin受体及ALK1受体共同介导的。本项目拟进一步明确心肌细胞通过旁分泌Inhibin调控心肌成纤维细胞的作用，并深入研究Inhibin调控心肌成纤维细胞激活的具体机制。同时，本项目拟探索增强体内Inhibin信号对于小鼠心肌纤维化的治疗潜力。本项目旨在阐明Inhibin在心肌病理性重塑中的表达模式、作用以及其背后的分子机制，为心肌纤维化的治疗提供新的理论依据。

Cardiac fibrosis appears in many kinds of heart diseases, which is an important cause of cardiac dysfunction and heart failure. This project first found that the expression of Inhibin increased during cardiac fibrosis in mice. Cardiomyocytes specific knockout Inhibin aggravated cardiac fibrosis induced by angiotensinⅡ in mice and deteriorated heart function. Cell experiments showed that Inhibin was expressed and secreted by cardiomyocytes under pathological stimuli, and inhibited the activation of cardiac fibroblasts. Further experiments showed that Inhibin can activate Smad1/5 signal and inhibit Smad2/3 signal in cardiac fibroblasts, and these effects may be mediated by the receptors Endoglin and ALK1. This project intends to further clarify the role of cardiomyocytes in regulating cardiac fibroblasts by paracrine Inhibin and further study the specific mechanism of Inhibin regulating the activation of cardiac fibroblasts. At the same time, this project intends to explore the therapeutic potential of enhancing Inhibin signal in vivo for cardiac fibrosis in mice. The purpose of this project is to clarify the expression pattern, function and molecular mechanism of Inhibin in cardiac pathological remodeling. It provides a new theoretical basis for the treatment of myocardial fibrosis and the prevention of heart failure.