Mitochondrial Protein HSG Is a Major Determinant of Oxid

程序性细胞死亡或细胞凋亡对大多数器官的发育以及成人组织的稳态和重塑都很重要。然而，终末分化心肌细胞的不可避免的损失是导致心力衰竭的一个关键因素，心力衰竭是目前发达国家死亡的主要原因。在这里，我们证明HSG（也称为mitofusin-2），一种线粒体蛋白，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（ROS）依赖机制在体内深刻地提高内源性HSG表达和心肌细胞凋亡。同样，H2O2氧化应激同时增加培养大鼠心肌细胞中HSG的表达和凋亡。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，并引发心肌细胞凋亡。通过抑制caspase-9而非caspase-8，以及表达组成型活性PI3K突变体激活Akt或线粒体抗凋亡蛋白Bcl-xL，可完全消除HSG诱导的心肌细胞凋亡，这表明HSG通过抑制PI3K-Akt细胞存活信号并由此激活线粒体主要凋亡途径来促进心肌细胞凋亡。重要的是，sirna介导的HSG沉默可以保护细胞免受氧化应激诱导的凋亡。本研究结果表明，心肌HSG通过抑制原代细胞存活信号Akt，激活线粒体细胞死亡通路，在心肌缺血和氧化应激反应中发挥心肌细胞凋亡的主要决定因素作用。重要的是，心脏HSG表达的增加对于氧化应激诱导的心肌细胞凋亡是必要和充分的，这表明HSG失调可能是心力衰竭的关键致病因素和有希望的治疗靶点。

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.