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导致的缺血性心脏病是最普遍的原因西方世界的发病率和死亡率。而生物活性甘油磷脂溶磷脂酸（LPA）在动脉粥样硬化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是未探索。急性心肌梗塞后，血清LPA浓度升高到六倍以控制受试者，表明LPA可能有助于心肌梗塞的发病机理。 LPA生产涉及分泌的酶自动西昔辛对溶物磷脂酰胆碱的水解，而脂质磷酸盐磷酸酶-3（LPP3）催化LPA去磷酸化产生不活跃的受体的脂质产物。在此应用中，我们提供了第一个证据，表明心脏缺血/再灌注（I/R）损伤增强了心肌自身肝素水平并降低心肌LPP3表达，这与增加有关血清LPA水平。再灌注后，活性氧的产生是从 I/R损伤后线粒体。氧化还原敏感的转录因子NFAT（活化T-的核因子细胞）已被证明与自身Xt蛋白启动子结合并诱导其表达。同样，氧化应激通过降低LPP3表达或增强的LPP3，可能在I/R损伤的背景下耗尽LPP3水平降解。因此，我们假设I/R损伤通过线粒体改变了自身赛和LPP3的表达超氧化物产生以驱动LPA信号传导和心肌细胞功能障碍。以下相互关联特定目的旨在在体外和实验中提供体外，体外的渐进和深入研究治疗设置。特定目标1将评估心肌超氧化物在自身赛素中的作用 I/R损伤代谢中的表达和LPA产生。特定目标2将确定线粒体的作用 I/R损伤中LPP3耗竭和LPA产生中的超氧化物产生。我们可以确定是否细胞与线粒体抗氧化剂状态的调节赋予I/R损伤的差异保护作用型号。