Role of Bnip3 in Myocardial Ischemia/Reperfusion

描述（由申请人提供）：细胞凋亡死亡被认为是缺血/再灌注（I/R）损伤的主要组成部分。I/R过程中细胞死亡通路的激活导致终分化心肌细胞的丢失，从而导致心力衰竭的发生。Bcl-2家族蛋白在调控心肌细胞凋亡的线粒体途径中发挥重要作用。BnipS是Bcl-2家族的促凋亡成员，主要定位于心肌细胞的线粒体。BnipS的过表达可导致包括新生儿心肌细胞在内的多种细胞类型的线粒体功能障碍和细胞死亡。在急性缺血和心力衰竭的动物模型中，BnipS蛋白水平升高已被报道。我们发现BnipS在成人心肌中大量表达，我们的初步数据表明BnipS通过激活线粒体途径在l/ r介导的细胞死亡中发挥重要作用。此外，我们发现BnipS的过表达会导致线粒体网络的广泛断裂，同时自噬上调，并且在缺氧或模拟I/R的细胞中，BnipS会发生蛋白水解。(8)。在本提案中，我们将探讨BnipS作为氧化还原传感器的假设，该传感器在I/R过程中被氧化应激激活，导致线粒体功能障碍和随后的细胞死亡。这一假设将探讨以下具体目的：1。探讨BnipS作为线粒体氧化应激传感器的作用2。定义BnipS介导线粒体断裂的分子机制3。阐明自噬在bnips介导的细胞死亡中的作用我们的长期目标是了解导致I/R损伤的途径，本提案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治疗或预防心脏病的新治疗靶点。

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.