Dysregulation of HSG Triggers Cardiomyocyte Apoptosis

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，不可阻挡的终末分化心肌细胞的丧失是心力衰竭发展的关键原因，心力衰竭目前是发达国家的主要死亡原因，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，识别调控心肌细胞凋亡的基因修饰物和分子机制一直是心血管生物学和医学领域的一个主要焦点，以揭示这种毁灭性心血管疾病的新的病因学见解和治疗靶点。我们最近发现了一种新的内源性RAS抑制基因，即增殖抑制基因(HSG)，又名大鼠丝裂原蛋白-2(rMfn-2)，源于它的人类同源基因MFn-2。尽管已有研究表明人类MFN-2及其同系物定位于线粒体外膜，在线粒体融合中发挥重要作用，但我们已证明HSG在体内和体外通过抑制Ras-ERK/MAPK信号通路而显示出深刻的抗增殖作用，并且rHSG下调参与了多种血管增生性疾病。 在这里，我们证明了线粒体蛋白HSG(也称为mitofusin-2)是心肌细胞凋亡的重要决定因素。在活体心肌缺血或氧化应激时，培养的大鼠心肌细胞内源性HSG的表达显著上调，当HSG过度表达时，会导致心肌细胞凋亡，表现为线粒体细胞色素c释放增加以及caspase-9和caspase-3的激活。HSG的促凋亡作用是通过抑制PI3K/Akt细胞生存信号来实现的，因为过量的HSG抑制了基础和血清诱导的Akt的激活。值得注意的是，结构活性突变体PI3K的表达可以阻止HSG诱导的细胞凋亡，而siRNA介导的HSG基因敲除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是临床上重要的缺血/氧化应激诱导的心脏病的关键介质，并表明基因敲除或抑制HSG功能可能为治疗目前缺乏有效治疗的破坏性疾病心力衰竭提供一种高效的新疗法。

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.