泛素连接酶ZSWIM8促进AGO2/miR-1复合物泛素化降解在缺血性心脏病中的作用及其机制研究

泛素-蛋白酶体系统紊乱在缺血性心脏病发生发展中起着重要作用，最新研究首次发现泛素E3连接酶ZSWIM8介导的泛素化修饰靶向microRNAs的快速降解。本项目前期结果发现，ZSWIM8在人类心脏和小鼠主要脏器均广泛表达，并且在心肌梗死后的人类和小鼠心肌组织中ZSWIM8的mRNA和蛋白水平表达均显著降低，在体试验观察到在小鼠缺血性心脏病模型中，过表达ZSWIM8后心肌细胞凋亡水平和纤维化水平显著降低，心梗面积显著减少，心功能显著改善，表明ZSWIM8具有潜在的抵抗心肌损伤作用。后续高通量筛选发现miR-1是其潜在靶点，因此本项目拟使用AAV9-构建心脏特异性过表达和敲减ZSWIM8模式小鼠，miR-1敲除小鼠，结合一系列体内体外实验共同探究ZSWIM8介导的泛素蛋白酶体通过促进AGO2/miR-1复合物的泛素化降解发挥缺血性心脏病的保护作用及其分子机制。

A number of studies had elucidated that the dysfunction of ubiquitin-proteasome system is involved in the pathogenesis of ischemia-induced myocardial injury. Recently, researchers first found that ubiquitin ligase enzyme ZSWIM8 contributed to the rapid ubiquitin-mediated degradation of microRNAs. Our preliminary results showed ZSWIM8 was ubiquitin expressed in heart tissue in human and mice. Furthermore, overexpression of ZSWIM8 in mice significantly decreased the cardiac myocyte apoptosis, moderated fibrosis level, and decreased myocardial infarct size after myocardial infarction, which suggested that ZSWIM8 might have a potential cardiac-protection role on myocardial infarction. The high-throughput experiments showed that miR-1 may be the target of ZSWIM8. In this study, we aim to investigate the effect of ZSWIM8 on myocardial infarction and the potential mechansim.