肾素（前体）受体调控缺血性心肌病的机制研究

项目名称： 肾素（前体）受体调控缺血性心肌病的机制研究

项目编号： No.81500304

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 刘岩

作者单位： 大连医科大学

项目金额： 18万元

中文摘要： 缺血性心肌病的发生机制尚未完全明确，心肌细胞丢失是重要原因之一。造成细胞丢失的原因包括凋亡和自噬，因其具有可调控性，有望成为改善心梗后心脏功能的切入点。肾素血管紧张素系统(RAS)的激活特别是血管紧张素II(AngⅡ)参与心衰的发病过程。肾素（前体）受体[(P)RR]是新近发现的跨膜蛋白，肾素及其前体与(P)RR结合具有激活RAS系统和非AngⅡ依赖的细胞信号通路等多重作用。申请人前期研究已证实(P)RR在心肌细胞中激活p38MAPK及PI3K/AKT通路参与缺氧复氧所致细胞凋亡（相关文章发表在Mol Cell Biochem. 2015）。本研究在此基础上，拟通过心脏特异性过表达(P)RR转基因小鼠，从动物和细胞水平探讨(P)RR对缺血性心肌病的调控作用和分子机制，旨在阐明(P)RR通过介导信号通路调控心肌自噬和凋亡，导致心梗后心衰的发生。为缺血性心肌病的临床防治提供新的靶点和理论基础。

中文关键词： 肾素（前体）受体；缺血性心肌病；细胞自噬；细胞凋亡；信号通路

英文摘要： Although the mechanism of ischemic cardiomyopathy is not entirely clear, cardiomyocyte loss is one of the important reasons. The cause of cell loss included apoptosis and autophagy, which can be regulated and is expected to become the breakthrough point to improve cardiac function after myocardial infarction. The activation of renin angiotensin system (RAS), especially for the elevation of angiotensin II (AngII), is involved in the pathogenic process of heart failure. The (pro)renin receptor [(P)RR] which is a new member of RAS, is a molecule that binds prorenin and renin in tissues, not only leading to their activation, but also acting as a signalling receptor for (pro)renin, independent of the formation of Ang II. Furthermore, (P)RR is also a subunit of Wnt signaling pathway. Our previous studies have shown that in cardiomyocytes (P)RR mediated p38MAPK and PI3K/AKT pathway played a vital role in cells apoptosis and secretion of inflammatory cytokines induced by hypoxia/reoxygenation. In this study, using cardiac specific expression (P)RR transgenic mice, we explore the effect of (P)RR on ischemic cardiomyopathy and its underlying molecular mechanisms from animal and cardiomyocytes level. We want to clarify that (P)RR-mediated signaling pathways regulated myocardial autophagy and apoptosis, and led to the occurrence of heart failure after myocardial infarction. We will offer a new target spot and theoretical basis for clinical prevention and treatment of ischemic cardiomyopathy.

英文关键词： (pro)renin receptor;ischemic cardiomyopathy ;autophagy;apoptosis;signal pathway