Mitochondrial Matrix Metalloproteinase-2 and Cardiac Injury

描述(由申请人提供)： 线粒体基质金属蛋白酶-2与心脏损伤基质金属蛋白酶对心脏结构和功能的调控已成为研究热点。在心脏损伤模型和心肌梗死或充血性心力衰竭的环境中，许多工作都集中在特定的基质金属蛋白酶(MMP-2)的活性上。在临床上，基质金属蛋白酶-2直接参与了进行性心室重构和充血性心力衰竭，进一步了解该酶的作用至关重要(S)。在这项提案中，我们提供了以前未被识别的细胞内基质金属蛋白酶-2(mito-基质金属蛋白酶-2)亚型的证据，该异构体特异性地针对线粒体。Mito-MMP2诱导线粒体到核的应激信号，激活核因子-B和活化T细胞核因子(NFAT)信号通路。这些信号级联反应诱导的基因是先天免疫系统的关键组成部分，包括促炎趋化因子和促凋亡因子，它们导致心肌细胞凋亡和炎性细胞浸润。表达MITO-MMP2的转基因小鼠在体外缺血/再灌注损伤后表现出进行性的心室肥厚、严重的收缩缺陷和加重的损伤。我们建议对mito-MMP2转基因小鼠的心脏病理生理学进行定量分析，并确定与心肌细胞凋亡和炎症有关的先天免疫基因激活的时间模式。此外，我们将确定mito-MMP2的线粒体蛋白分解靶点，并评估该酶对心肌线粒体生物能量学和心室收缩功能的影响。这些研究有望为进行性心力衰竭的病理生理学提供新的见解，并可能为这种常见的严重致残性疾病的治疗干预提供新的机会。 公共卫生相关性： 心血管疾病是退伍军人事务部医学中心治疗的退伍军人中最常见的死因。此外，由心室泵血能力缺陷引起的充血性心力衰竭是导致退伍军人发病率和死亡率的主要因素。我们的工作表明，一种新的分子有助于心脏损伤，并为这种常见的致残障碍提供了新的治疗形式的可能性。

DESCRIPTION (provided by applicant): Mitochondrial Matrix Metalloproteinase-2 and Cardiac Injury Modulation of cardiac structure and function by matrix metalloproteinases (MMP) has become an area of intense interest. Much effort has been focused on the activity of a specific MMP, (MMP-2), in models of cardiac injury and in the settings of myocardial infarction or congestive heart failure. Clinically, MMP-2 directly contributes to progressive ventricular remodeling and congestive heart failure and a further understanding of the role(s) of this enzyme is critically important. In this Proposal we provide evidence for a previously unrecognized intracellular isoform of MMP-2 (mito-MMP-2) that specifically targets mitochondria. Mito-MMP-2 induces mitochondria-to-nuclear stress signaling, with activation of NF-:B and Nuclear Factor of Activated T-cell (NFAT) signaling cascades. Genes induced by these signaling cascades are critical components of the innate immune system and include pro-inflammatory chemokines and pro-apoptotic factors which lead to cardiomyocyte apoptosis and inflammatory cell infiltration. Transgenic mice expressing mito-MMP-2 exhibit progressive ventricular hypertrophy, severe contractile defects and enhanced injury following ex vivo ischemia/reperfusion injury. We propose to perform a quantitative analysis of the cardiac pathophysiology of the mito-MMP-2 transgenic mice and to determine the temporal pattern of activation of innate immunity genes which contribute to cardiomyocyte apoptosis and inflammation. Further, we will determine the mitochondrial proteolytic targets of mito-MMP-2 and assess the effects of this enzyme on cardiac mitochondrial bioenergetics and ventricular contractile function. These studies will hopefully provide new insights into the pathophysiology of progressive ventricular failure and possibly present new opportunities for therapeutic intervention for this common and severely disabling disorder. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is most common cause of death in veterans treated by the Department of Veterans Affairs Medical Centers. In addition, congestive heart failure caused by defects in the pumping ability of the heart ventricles is a leading contributor to morbidity and mortality in the veteran population. Our work suggests that a new molecule contributes to heart injury and offers the possibility of new forms of therapy for this common and disabling disorder.