Role of Bnip3 in Myocardial Ischemia/Reperfusion

描述（由申请人提供）：细胞凋亡导致的细胞死亡被认为是缺血/再灌注（I/R）损伤的主要组成部分。I/R期间细胞死亡途径的激活导致终末分化的心肌细胞的损失，从而促进心力衰竭的发展。Bcl-2家族蛋白在调节心肌细胞凋亡的线粒体途径中起重要作用。BnipS是Bcl-2家族的促凋亡成员，主要定位于心肌细胞中的线粒体。BnipS的过表达导致各种细胞类型中的线粒体功能障碍和细胞死亡，包括新生心肌细胞。在急性缺血和心力衰竭的动物模型中，体内BnipS蛋白水平升高。我们已经发现BnipS基本上在成年心肌中表达，并且我们的初步数据表明BnipS通过激活线粒体途径在I/R介导的细胞死亡中起重要作用。此外，我们已经发现BnipS的过表达导致线粒体网络的广泛断裂沿着自噬的上调，并且BnipS在经受缺氧或模拟I/R的细胞中经受蛋白水解。（八）、在这项提案中，我们将探讨BnipS作为氧化还原传感器的功能，在I/R过程中增加氧化应激激活，导致线粒体功能障碍和随后的细胞死亡的假设。这一假设将探讨以下具体目标：1。研究BnipS作为氧化应激的线粒体传感器的作用2.定义BnipS介导线粒体片段化的分子机制3.阐明自噬在Bnips介导的细胞死亡中的作用4.我们的长期目标是了解导致I/R损伤的途径，这项提议的结果将为心脏细胞凋亡途径及其调控提供新的见解。进一步了解BnipS在心脏中的功能有可能确定新的治疗靶点来治疗或预防心脏病。

DESCRIPTION (provided by applicant): Cell death by apoptosis is recognized as a major component of ischemia/reperfusion (I/R) injury. Activation of cell death pathways during I/R leads to loss of terminally differentiated cardiac myocytes, thus contributing to the development of heart failure. The Bcl-2 family proteins play an important role in regulating the mitochondrial pathway of apoptosis in the myocardium. BnipS is a pro-apoptotic member of the Bcl-2 family and is localized primarily to the mitochondria in myocardial cells. Overexpression of BnipS leads to mitochondrial dysfunction and cell death in various cell types, including neonatal cardiac myocytes. Elevated levels of BnipS protein have been reported in vivo in animal models of acute ischemia and heart failure. We have found that BnipS is expressed at substantially in the adult myocardium and our preliminary data indicate that BnipS plays a significant role in l/R-mediated cell death by activation of the mitochondrial pathway. Moreover, we have found that overexpression of BnipS causes extensive fragmentation of the mitochondrial network along with upregulation of autophagy, and that BnipS is subjected to proteolysis in cells subjected to hypoxia or simulated I/R. (8). In this proposal, we will explore the hypothesis that BnipS functions as a redox sensor that is activated by increased oxidative stress during I/R, leading to mitochondrial dysfunction and subsequent cell death. This hypothesis will be explored with the following specific aims: 1. Investigate the role of BnipS as a mitochondrial sensor of oxidative stress 2. Define the molecular mechanism(s) by which BnipS mediates mitochondrial fragmentation 3. Elucidate the role of autophagy in BnipS-mediated cell death 4. Characterize the role of BnipS proteolysis in response to I/R Our long-term goal is to understand the pathways that contribute to I/R injury and the results from this proposal will provide new insights into the pathways of apoptosis and their regulation in the heart. Further understanding of how BnipS functions in the heart has the potential to identify new therapeutic targets to treat or prevent heart disease.