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 慢性长期滥用酒精会导致心肌功能障碍并导致心力衰竭。这 酒精导致心脏损伤的机制尚不清楚。线粒体功能障碍起着 由于细胞的变化，在酒精性心肌病的发展和并发症中发挥着重要作用 血脂水平。在细胞培养模型中，溶血磷脂酸 (LPA) 信号传导升高会诱导 心肌细胞功能障碍（增强心房钠尿肽 [ANP] 和脑钠尿肽 [BNP] 表达）。溶血磷脂酸的产生涉及分泌的溶血磷脂酰胆碱的水解 自分泌运动因子，而脂质磷酸磷酸酶 3 (LPP3) 催化溶血磷脂酸 去磷酸化产生不具有受体活性的脂质产物。在这个应用程序中，我们提出了 第一个证据表明大量饮酒会提高心肌自分泌运动因子水平并降低 LPP3 表达，这与溶血磷脂酸信号传导增加有关。我们推测，基于 大量饮酒，氧化还原敏感转录因子 NFAT（激活 T 细胞的核因子） 与自分泌运动因子启动子结合并诱导其表达。此外，酒精会反式激活 microRNA-92a， 它是 LPP3 的负调节因子。因此，我们假设大量饮酒会改变自分泌运动因子 和 LPP3 表达驱动溶血磷脂酸信号传导和心肌功能障碍。下列 相互关联的具体目标旨在提供逐步深入的体外、体内和体内研究 实验治疗设置。具体目标 1 将评估酒精诱导的自分泌运动因子表达的作用 和心肌中溶血磷脂酸的产生。具体目标 2 将确定酒精的作用 - 介导心肌中 LPP3 耗竭和溶血磷脂酸调节。我们可以确定是否 细胞外与细胞内抗氧化状态的调节赋予不同的保护作用 大量饮酒。这项研究不仅会加深我们对酒精的理解 自分泌运动因子-LPA-LPP3 介导心力衰竭，但也将为未来的临床干预确定新的靶点。