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Alcohol mediated myocardial lysophosphatidic acid signaling

酒精介导的心肌溶血磷脂酸信号传导

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

摘要