β-arrestins保护心肌梗死的作用和机制研究

Myocardial infarction (MI) and ensuing heart failure area major threat to our health. Adverse myocardial remodeling of post-MI hearts results in cardiac dysfunction. In recent years, it has been reported that after MI, the activation of sympathetic/adrenergic nervous system (SAS) and renin-angiotensin system (RAS) exerts a cardioprotective effect through β-arrestin-dependent signaling pathways. However, the underlying mechanism remains unclear. Moreover, it has been reported that after MI, autophagy in cardiomyocytes is enhanced, which may contribute to cardioprotection and improve the prognosis of MI. Our preliminary study showed that cardiomyocyte-specific knockout of β-arrestin-1 results in worse cardiac remodeling and function after MI, which was associated with reduced cardiomyocyte autophagy. This project aims to study direct protective effects of β-arrestins on stressed cardiomyocytes with cultured cardiomyocytes, ex vivo hearts and in vivo MI models. We will further explore the upstream mechanisms that activate β-arrestin-dependent signaling pathways via G-protein coupled receptors as well as the downstream mechanism regulating autophagy in stressed cardiomyocytes and hearts. This study will provide novel insight for developing β-arrestin-biased drugs to treat heart failure.

心梗及其并发症心衰是威胁人类健康的重大疾病，心梗后心脏的不良重构是导致心功能恶化的重要因素。近来研究表明心梗后交感肾上腺素能神经系统（SAS）和肾素-血管紧张素系统（RAS）激活可以通过β-arrestins信号产生心脏保护作用，但机制不清。此外，研究发现心梗后心肌细胞自噬增强，且对心梗预后有保护作用。我们发现心肌细胞β-arrestin-1条件敲除后心梗预后变差，其机制与抑制β-arrestin-1介导的心肌细胞自噬有关。本项目拟在细胞、器官及整体动物水平研究β-arrestins对心肌细胞的直接保护作用，并探索激活β-arrestins信号的上游受体机制，及其下游与自噬的关系。本研究将为开发具有β-arrestins偏向性的心衰治疗药物提供思路。

心梗后心脏的不良重构是导致心功能恶化的重要因素。研究表明心梗后交感肾上腺素能神经系统（SAS）和肾素-血管紧张素系统（RAS）激活可以通过β-arrestins信号产生心脏保护作用，但机制不清。在本项目执行过程中，申请人根据前期研究基础，着重围绕“β-arrestin1、自噬、心脏保护效应”三者展开研究，发现：1）β-arrestin1对缺血心肌细胞具有保护作用；2）β-arrestin1能够促进心肌细胞自噬增强；3）心肌细胞β-arrestin1通过促进自噬介导其心脏保护效应。4）阐明β-arrestin1促进自噬的信号机制，即β-arrestin1通过桥连LKB1-ERK1/2蛋白，进而激活AMPK-mTOR-S6K1信号通路促进自噬，发挥心脏保护效应。在该项目的资助下，我们发表SCI论文7篇，目前修回1篇（均为第一标注），其中影响因子大于5的有4篇；申请国家发明专利2项，目前授权1项；培养博士研究生和硕士研究生6名；项目负责人获得2018年“上海市浦江人才”及上海市科技进步一等奖1项；项目负责人参加《自噬研究指南2016》的国际指南编写1次；总体来看，该项目圆满完成任务。