Alcohol mediated myocardial lysophosphatidic acid signaling

酒精介导的心肌溶血磷脂酸信号传导

• 批准号: 9896130
• 负责人: Manikandan Panchatcharam
• 金额: $ 20.99万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896130
• 关键词: 3' Untranslated Regions; Address; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Cardiomyopathy; Alcohols; American; Antioxidants; Applications Grants; Atrial Natriuretic Factor; Binding; Binding Sites; Biological Models; Blood; Body Weight; Brain natriuretic peptide; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Culture Techniques; Chronic; Clinical; Data; Development; Disease; Dose; Enzymes; Ethanol; Event; Exposure to; Fibrosis; Functional disorder; Future; Health; Heart; Heart failure; Heavy Drinking; Hydrolysis; Hypertrophy; Impairment; In Vitro; Ingestion; Intervention; Investigational Therapies; Link; Lipids; Liver; Liver diseases; Luciferases; Lysophosphatidic Acid Receptors; Lysophosphatidylcholines; Mediating; Mental disorders; Messenger RNA; MicroRNAs; Mitochondria; Modeling; Morbidity - disease rate; Mus; Muscle Cells; Mutate; Myocardial; Myocardial dysfunction; Myocardium; Necrosis; Neuraxis; Normal tissue morphology; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Play; Production; Protein Dephosphorylation; Public Health; Reactive Oxygen Species; Regulation; Reporter; Reporting; Role; Signal Transduction; Source; Superoxide Dismutase; Testing; Transcriptional Regulation; Translations; United States National Institutes of Health; alcohol exposure; cell type; design; extracellular; heart damage; in vivo; inhibitor/antagonist; insight; interstitial; lipid phosphate phosphatase; lysophosphatidic acid; man; mimetics; mitochondrial dysfunction; mortality; novel; nuclear factors of activated T-cells; offspring; oxidant stress; problem drinker; promoter; protective effect; response; tissue injury; transcription factor

Abstract Chronic long-term abuse of alcohol leads to myocardial dysfunction and results in heart failure. The mechanism by which alcohol causes cardiac damage remains unclear. Mitochondrial dysfunction plays a significant role in the development and complications of alcoholic cardiomyopathy due to changes in cellular lipid levels. In cell culture models, elevated lysophosphatidic acid (LPA) signaling induces markers of cardiomyocyte dysfunction (enhanced Atrial natriuretic peptide [ANP] and brain natriuretic peptide [BNP] expression). Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that heavy alcohol consumption enhances the myocardial autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. We speculate that upon heavy alcohol consumption, the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) bind to the autotaxin promoter and induce its expression. Furthermore, alcohol transactivates microRNA-92a, which is a negative regulator of LPP3. Thus, we hypothesize that heavy alcohol consumption alters autotaxin and LPP3 expression to drive lysophosphatidic acid signaling and myocardial 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 alcohol-induced autotaxin expression and lysophosphatidic acid production in the myocardium. Specific Aim 2 will determine the role of alcohol- mediated LPP3 depletion and lysophosphatidic acid regulation in the myocardium. We could identify whether modulation of extracellular versus intracellular antioxidant status confers a differential protective effect upon exposure to heavy alcohol consumption. This study will not only extend our understanding of alcohol- autotaxin-LPA-LPP3 mediated cardiac failure but will also identify novel targets for future clinical interventions.

抽象的 长期滥用酒精会导致心肌功能障碍并导致心力衰竭。这 酒精造成心脏损伤的机制尚不清楚。线粒体功能障碍播放 由于细胞的变化而导致酒精性心肌病的发育和并发症的重要作用 脂质水平。在细胞培养模型中，升高的溶血磷脂酸（LPA）信号传导可诱导 心肌细胞功能障碍（增强的心dimatiration肽[ANP]和脑纳替肽[BNP] 表达）。溶血磷脂酸的产生涉及分泌的溶血磷脂酰胆碱水解 酶自身赛，而脂质磷酸磷酸盐磷酸酶-3（LPP3）催化溶血磷脂酸 去磷酸化以产生不活跃的受体的脂质产物。在此应用程序中，我们提出 首先证明大量饮酒会增强心肌自身赛素水平并降低LPP3 表达，这与溶物磷酸酸信号的增加有关。我们推测 大量酒精消耗，对氧化还原敏感的转录因子NFAT（活化T细胞的核因子） 结合自型蛋白启动子并诱导其表达。此外，酒精反式激活microRNA-92A， 这是LPP3的负调节剂。因此，我们假设大量饮酒会改变自身赛素 和LPP3表达以驱动溶物磷脂酸信号传导和心肌功能障碍。下列 相互关联的特定目的旨在在体外，体内以及在体外提供渐进和深入研究 实验治疗设置。特定的目标1将评估酒精诱导的自身表达的作用 并在心肌中产生溶血磷脂酸。特定的目标2将决定酒精的作用 心肌中介导的LPP3耗竭和溶物磷脂酸调节。我们可以确定是否 细胞外与细胞内抗氧化剂状态的调节赋予了差异保护作用 暴露于大量饮酒。这项研究不仅会扩展我们对酒精的理解 - 自Xt蛋白LPA-LPP3介导的心脏衰竭，但还将确定未来临床干预措施的新目标。