Dysregulation of HSG Triggers Cardiomyocyte Apoptosis

程序性细胞死亡或凋亡对于大多数器官的发育以及成体组织的稳态和重塑都是重要的。然而，终末分化的心肌细胞的不可阻挡的损失是心力衰竭发展的关键原因，心力衰竭是发达国家目前的主要死亡原因，预计到2020年将成为全球头号杀手，但心力衰竭目前缺乏有效的治疗方法。因此，识别基因修饰物和心肌细胞凋亡的分子机制一直是心血管生物学和医学的主要焦点，以揭示新的病因学见解和治疗靶点的毁灭性心血管疾病。我们最近发现了一个新的内源性Ras抑制剂，增生抑制基因（HSG），也被命名为大鼠线粒体融合蛋白-2（rMfn-2）后，其人类同源物线粒体融合蛋白-2（Mfn-2）。尽管先前的研究表明人Mfn-2及其同源物定位于线粒体外膜并在线粒体融合中起重要作用，但我们已经证明HSG通过抑制Ras-ERK/MAPK信号通路在体内和体外表现出深刻的抗增殖作用，并且下调rHSG有助于各种血管增殖性疾病。 在这里，我们证明，HSG（也称为mitofusin-2），线粒体蛋白，是心肌细胞凋亡的重要决定因素。内源性HSG表达在体内心肌缺血或培养的大鼠心肌细胞中的氧化应激过程中显著上调，并且当过表达时引起心肌细胞凋亡，如通过增加线粒体细胞色素c释放和caspase-9和caspase-3的活化所表现的。HSG的促凋亡作用是通过抑制PI 3 K/Akt细胞存活信号介导的，因为过量的HSG抑制Akt的基础和血清诱导的活化。值得注意的是，组成型活性突变体PI 3 K的表达防止HSG诱导的细胞凋亡，并且siRNA介导的HSG基因敲低有效地保护细胞免受氧化应激诱导的细胞凋亡。这些发现标志着HSG作为临床上重要的缺血/氧化应激诱导的心脏病的关键介质，并表明基因敲低或抑制HSG功能可能提供一种非常有效的新疗法，用于治疗目前缺乏有效疗法的破坏性疾病心力衰竭。

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 pivotal causal factor for the development of heart failure, the current leading cause of death in developed countries and the predicted number one killer worldwide by 2020, but heart failure currently lacks effective therapies. Thus, identifying genetic modifiers and molecular mechanisms governing heart muscle cell apoptosis has been a major focus in cardiovascular biology and medicine in order to reveal new etiological insights and therapeutic targets for the devastating cardiovascular disease. WE have recently identified a novel endogenous Ras inhibitor, hyperplasia suppressor gene (HSG), also named rat mitofusin-2 (rMfn-2) after its human homologue mitofusin-2 (Mfn-2). Although previous studies have shown that human Mfn-2 and its homologues localize to the mitochondrial outer membrane and play an essential role in mitochondrial fusion, we have demonstrated that HSG exhibits profound anti-proliferative effects in vivo and in vitro via inhibiting the Ras-ERK/MAPK signaling pathway, and that downregulation of rHSG contributes to various vascular proliferative disorders. Here, we demonstrate that HSG (also named mitofusin-2), a mitochondria protein, is an important determinant of heart muscle cell apoptosis. Endogenous HSG expression is profoundly upregulated during myocardial ischemia in vivo or oxidative stress in cultured rat cardiomyocytes, and causes cardiomyocyte apoptosis when overexpressed, as manifested by increased mitochondrial cytochrome c release and activation of caspase-9 and caspase-3. The pro-apoptotic effect of HSG is mediated by inhibiting of PI3K/Akt cell survival signal, since excessive HSG inhibits both basal and serum-induced activation of Akt. Remarkably, expression of a constitutively active mutant PI3K prevents HSG-induced apoptosis, and siRNA-mediated gene knockdown of HSG effectively protects cells against oxidative stress-induced apoptosis. These findings marks HSG as a crucial mediator of clinically important ischemia/oxidative stress-induced heart disease, and suggest gene knockdown or inhibition of HSG function might provide a highly effective novel therapy in treating the devastating disease, heart failure, that currently lacks effective therapies.