糜酶调节CFs功能影响心肌梗死后左心室重构的机制研究

Left ventricular remodeling after myocardial infarction (MI) is closely correlated with myocardial fibrosis, which mainly involves the number and function changes of cardiac fibroblasts (CFs), resulting in the metabolic changes of extracellular matrix (ECM). The increase release of chymase by mast cell after MI could affect ventricular remodeling by modulating the function of CFs, but the mechanism by which it functions remains further illustration. Our study aims to ①measure levels and gene expressions of chymase in mice with left anterior descending artery ligation-induced MI, evaluate the correlation between chymase and CFs activity and cardiac function parameters, and explore the effect of chymase on TGF-β1/Smad signaling pathway and its downstream effectors of CTGF and PAI-1; ②observe the effect of blocking chymase pathway on cardiac parameters of mice MI models and differentiation in vitro activity of CFs by using its specific inhibitor or gene knockout mice. This study is expected to further clarify the role and mechanism of chymase in left ventricular remodeling after MI, and provide new theoretical basis and experimental evidence for treatment of myocardial fibrosis and ventricular remodeling after MI.

心肌梗死（MI）后左心室重构与心肌纤维化密切相关，心肌纤维化主要表现为心脏成纤维细胞（CFs）数量和功能改变，进而引起细胞外基质（ECM）代谢发生变化。MI后肥大细胞释放糜酶增多，能够通过调节CFs功能影响心室重构，但作用和机制有待进一步阐明。本课题拟①制备小鼠MI模型，测定糜酶在小鼠MI后不同时间点体内的含量及基因表达水平，评价糜酶与MI后CFs活性及心功能指标的相关性，研究糜酶对TGF-β1/Smad信号通路及下游效应因子CTGF和PAI-1的作用；②通过应用糜酶特异性抑制剂或相关基因敲除小鼠阻断其作用通路，观察阻断糜酶作用通路对小鼠MI模型心功能及体外培养CFs分化活性的影响。该研究有望进一步阐明糜酶在MI后左心室重构中的作用和机制，将为MI后心肌纤维化和心室重构的治疗提供新的理论基础和实验依据。

心肌梗死（MI）后左心室重构与心肌纤维化密切相关，心肌纤维化主要表现为心脏成纤维细胞（CFs）数量和功能改变，进而引起细胞外基质（ECM）代谢发生变化。MI后肥大细胞释放糜酶增多，能够通过调节CFs功能影响心室重构，但作用和机制有待进一步阐明。本课题拟①制备小鼠MI模型，测定糜酶在小鼠MI后不同时间点体内的含量及基因表达水平，评价糜酶与MI后CFs活性及心功能指标的相关性，研究糜酶对TGF-β1/Smad信号通路及下游效应因子CTGF和PAI-1的作用；②通过应用糜酶特异性抑制剂或相关基因敲除小鼠阻断其作用通路，观察阻断糜酶作用通路对小鼠MI模型心功能及体外培养CFs分化活性的影响。该研究有望进一步阐明糜酶在MI后左心室重构中的作用和机制，将为MI后心肌纤维化和心室重构的治疗提供新的理论基础和实验依据。