Oxidative stress mediated myocardial lipid dysfunction

氧化应激介导的心肌脂质功能障碍

基本信息

批准号：
10331751
负责人：
Manikandan Panchatcharam
金额：
$ 21.55万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10331751
关键词：
Acute myocardial infarction Address Affect Antioxidants Applications Grants Atherosclerosis Atrial Natriuretic Factor Binding Biological Models Biology Brain natriuretic peptide Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Culture Techniques Cell Survival Centers of Research Excellence Clinical Data Enzymes Functional disorder Future Generations Genes Genetic Transcription Glycerophospholipids Heart Mitochondria Hydrolysis Hypoxia In Vitro Intervention Investigational Therapies Ischemia Knockout Mice Laboratories Lipids Luciferases Lysophosphatidic Acid Receptors Lysophosphatidylcholines Mediating Messenger RNA Metabolism Mission Mitochondria Modeling Morbidity - disease rate Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Oxidation-Reduction Oxidative Stress Oxygen Pathogenesis Pathway interactions Pharmacology Phosphoric Monoester Hydrolases Play Production Protein Dephosphorylation Reactive Oxygen Species Regulation Reperfusion Injury Reperfusion Therapy Reporter Role Serum Signal Transduction Source Stress Superoxide Dismutase Superoxides Testing Tissues Western World cell type design factor A in vivo inhibitor inorganic phosphate lipid phosphate phosphatase lysophosphatidic acid mimetics mitochondrial dysfunction mortality novel nuclear factors of activated T-cells oxidant stress promoter protective effect response transcription factor viral rescue virtual

项目摘要

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.

项目摘要急性心肌梗塞和由此产生的缺血性心脏病是导致心脏病的最常见原因。西方世界的发病率和死亡率。而具有生物活性的甘油磷脂溶血磷脂酸 (LPA) 在动脉粥样硬化疾病中发挥着众所周知的作用，但其在心肌功能中的作用实际上仍然存在未经探索。急性心肌梗塞后，血清 LPA 浓度比对照升高六倍受试者，表明 LPA 可能有助于心肌梗塞的发病机制。 LPA 生产涉及溶血磷脂酰胆碱被分泌酶自分泌运动蛋白水解，而脂质磷酸盐磷酸酶 3 (LPP3) 催化 LPA 去磷酸化，生成不具有受体活性的脂质产物。在此应用中，我们提出了第一个证据表明心脏缺血/再灌注 (I/R) 损伤会增强心肌自分泌运动因子水平并降低心肌 LPP3 表达，这与增加血清 LPA 水平。再灌注后，活性氧的产生会随着超氧化物的爆发而产生 I/R 损伤后的线粒体。氧化还原敏感转录因子 NFAT（激活 T-的核因子）细胞）已被证明可以与自分泌运动因子启动子结合并诱导其表达。同样，氧化应激可能会通过减少 LPP3 表达或增强 LPP3 来降低 I/R 损伤情况下的 LPP3 水平降解。因此，我们假设 I/R 损伤通过线粒体改变自分泌运动因子和 LPP3 的表达。超氧化物的产生可驱动 LPA 信号传导和心肌细胞功能障碍。以下是相互关联的具体目标旨在提供逐步深入的体外、体内和实验研究治疗设置。具体目标 1 将评估心肌超氧化物产生在自分泌运动因子中的作用 I/R 损伤代谢中的表达和 LPA 产生。具体目标2将确定线粒体的作用 LPP3 耗竭中的超氧化物产生和 I/R 损伤中的 LPA 产生。我们可以确定是否细胞与线粒体抗氧化状态的调节对 I/R 损伤具有不同的保护作用模型。