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最常见的单一原因 西方世界的发病率和死亡率。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发挥着众所周知的作用，但其在心肌功能中的作用几乎仍然存在 未被开发的。急性心肌梗死后，血清LPA浓度较对照组升高6倍 提示LPA可能参与了心肌梗死的发病机制。LPA生产涉及到 溶血磷脂酰胆碱由分泌酶自体趋化蛋白降解，而磷脂 磷酸酶-3(LPP3)催化LPA去磷酸化生成非受体活性的脂类产物。 在这一应用中，我们提出了心脏缺血/再灌注(I/R)损伤增强的第一个证据 心肌细胞自体趋化素水平和心肌LPP3表达减少，这与心肌细胞LPP3表达增加有关 血清LPA水平。在再灌流时，活性氧物种的产生是以超氧化物从 I/R损伤后线粒体。氧化还原敏感转录因子NFAT(活化T细胞的核因子) 细胞)已被证明与自体趋化蛋白启动子结合并诱导其表达。同样，氧化应激 在I/R损伤中可能通过减少LPP3表达或增强LPP3来耗尽LPP3水平 退化。因此，我们假设I/R损伤通过线粒体改变了自体趋化蛋白和LPP3的表达 产生超氧化物以驱动LPA信号和心肌细胞功能障碍。以下是相互关联的 具体目标是在体外、体内和实验中提供循序渐进和深入的研究 治疗机构。特异性目标1将评估心肌超氧化物产生在自体趋化中的作用 I/R损伤代谢中LPA的表达和产生特异靶2将决定线粒体的作用 LPP3耗竭时产生的超氧化物和I/R损伤时产生的LPA。我们可以确定是否 细胞和线粒体抗氧化状态的调节在I/R损伤中具有不同的保护作用 模特们。

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.