Oxidative stress mediated myocardial lipid dysfunction

项目摘要 急性心肌梗死和由此导致的缺血性心脏病是心肌梗死的最常见原因。 发病率和死亡率在西方世界。而生物活性甘油磷脂溶血磷脂酸 (LPA)在动脉粥样硬化性疾病中起着众所周知的作用，其在心肌功能中的作用实际上仍然存在 未开发的急性心肌梗死后血清LPA浓度升高6倍 提示LPA可能参与心肌梗死的发病机制。LPA生产涉及 溶血磷脂酰胆碱被分泌的自分泌运动因子水解，而脂质磷酸 磷酸酶-3（LPP 3）催化LPA去磷酸化以产生非受体活性的脂质产物。 在本申请中，我们提出了第一个证据表明，心脏缺血/再灌注（I/R）损伤增强 心肌自分泌运动因子水平和降低心肌LPP 3表达，这与心肌自分泌运动因子水平升高有关。 血清LPA水平在再灌注时，活性氧物质的产生作为超氧化物的爆发而出现， I/R损伤后的线粒体。氧化还原敏感性转录因子NFAT（活化T细胞的核因子， 细胞）结合自分泌运动因子启动子并诱导其表达。同样，氧化应激 在I/R损伤的情况下，通过降低LPP 3表达或增强LPP 3 降解因此，我们假设I/R损伤通过线粒体膜途径改变了自分泌运动因子和LPP 3的表达。 超氧化物产生驱动LPA信号传导和心肌细胞功能障碍。以下相互关联的 具体的目标是提供逐步和深入的研究，在体外，在体内，和在实验中， 治疗设置。具体目标1将评估心肌超氧化物产生在自运动因子中的作用 I/R损伤代谢中LPA的表达和产生。具体目标2将决定线粒体的作用， 在LPP 3耗竭中产生超氧化物和在I/R损伤中产生LPA。我们就能确定 细胞与线粒体抗氧化状态的调节赋予I/R损伤不同的保护作用 模型

Project Abstract Acute myocardial infarction and resulting ischemic heart disease are the single most prevalent cause of morbidity and mortality in the western world. While the bioactive glycerophospholipid lysophosphatidic acid (LPA) plays a well-known role in atherosclerotic disease, its role in myocardial function remains virtually unexplored. Following acute myocardial infarction, serum LPA concentration rises by six-fold over control subjects, suggesting LPA may contribute to the pathogenesis of myocardial infarction. LPA production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes LPA dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that cardiac ischemia/reperfusion (I/R) injury enhances myocardial autotaxin levels and decreases myocardial LPP3 expression, and this is associated with increased serum LPA levels. Upon reperfusion, reactive oxygen species production arises as a burst of superoxide from mitochondria following I/R injury. The redox-sensitive transcription factor NFAT (a nuclear factor of activated T- cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of I/R injury through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that I/R injury alters autotaxin and LPP3 expression through mitochondrial superoxide production to drive LPA signaling and cardiomyocyte dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific aim 1 will assess the role of myocardial superoxide production in autotaxin expression and LPA production in I/R injury metabolism. Specific aim 2 will determine the role of mitochondrial superoxide production in LPP3 depletion and LPA production in I/R injury. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect in I/R injury models.