Mitochondrial Protein HSG Is a Major Determinant of Oxid

线粒体蛋白 HSG 是氧化的主要决定因素

• 批准号: 7327023
• 负责人: Rui-Ping Xiao
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7327023
• 关键词: Mitochondrial; Protein; HSG; Major; Determinant

Programmed cell death, or apoptosis, is important for the development of most organs also for adult tissue homeostasis and remodeling. However, an inexorable loss of terminally differentiated heart muscle cells is a crucial causal factor for heart failure, the current leading cause of death in developed countries. Here, we demonstrate that HSG (also named mitofusin-2), a mitochondria protein, is a major determinant of oxidative stress-mediated cardiomyocyte apoptosis. Myocardial infarction profoundly elevates endogenous HSG expression and myocyte apoptosis in vivo via a reactive oxygen species (ROS)-dependent mechanism. Similarly, oxidative stress with H2O2 concurrently increases HSG expression and apoptosis in cultured rat cardiomyocytes. Furthermore, adenoviral gene transfer-mediated overexpression of HSG is sufficient to suppress both basal and serum-stimulated Akt activation, and triggers robust cardiomyocyte apoptosis. The HSG-induced apoptosis is fully abrogated by inhibition of caspase-9 but not caspase-8, and by expression of a constitutively active PI3K mutant to activate Akt or a mitochondrial antiapoptotic protein, Bcl-xL, indicating that HSG promotes cardiomyocytes apoptosis via inhibition of the PI3K-Akt cell survival signaling and the resultant activation of the primary mitochondrial apoptotic pathway. Importantly, siRNA-mediated HSG silencing protects cells against oxidative stress-induced apoptosis. The present results indicate that cardiac HSG functions as a major determinant of heart muscle cell apoptosis in response to ischemia and oxidative stress, via inhibiting the primary cell survival signal, Akt, resulting in activation of the mitochondrial cell death pathway. Importantly, increased cardiac HSG expression is both necessary and sufficient for oxidative stress-induced heart muscle cell apoptosis, suggesting that HSG deregulation may be a crucial pathogenic element and a promising therapeutic target for heart failure.

程序性细胞死亡，或称细胞凋亡，对大多数器官的发育以及成人组织的动态平衡和重塑都很重要。然而，终末分化的心肌细胞的不可阻挡的丧失是心力衰竭的关键原因，心力衰竭是目前发达国家的主要死亡原因。在这里，我们证明了线粒体蛋白HSG(也称为mitofusin-2)是氧化应激介导的心肌细胞凋亡的主要决定因素。心肌梗死通过活性氧簇(ROS)依赖机制在体内显著增加内源性HSG的表达和心肌细胞的凋亡。同样，过氧化氢的氧化应激同时增加培养的大鼠心肌细胞HSG的表达和细胞的凋亡。此外，腺病毒基因转移介导的HSG过表达足以抑制基础和血清刺激的Akt激活，并触发强大的心肌细胞凋亡。HSG诱导的心肌细胞凋亡可通过抑制caspase-9而不是caspase-8，以及通过表达固有活性的PI3K突变体来激活Akt或线粒体抗凋亡蛋白Bclxl而被完全消除，这表明HSG通过抑制PI3K-Akt细胞生存信号和由此激活主要的线粒体凋亡途径来促进心肌细胞的凋亡。重要的是，siRNA介导的HSG沉默保护细胞免受氧化应激诱导的细胞凋亡。目前的结果表明，心肌HSG通过抑制细胞存活信号Akt，激活线粒体细胞死亡途径，成为心肌细胞对缺血和氧化应激反应中细胞凋亡的主要决定因素。重要的是，心肌HSG表达增加是氧化应激诱导心肌细胞凋亡的必要条件和充分条件，提示HSG失控可能是心力衰竭的一个重要致病因素和一个有前途的治疗靶点。