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:
- 金额:$ 20.99万
- 依托单位:
- 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:
- 关键词:3&apos Untranslated RegionsAddressAffectAlcohol abuseAlcohol consumptionAlcoholic CardiomyopathyAlcoholsAmericanAntioxidantsApplications GrantsAtrial Natriuretic FactorBindingBinding SitesBiological ModelsBloodBody WeightBrain natriuretic peptideCardiacCardiac MyocytesCardiovascular DiseasesCell Culture TechniquesChronicClinicalDataDevelopmentDiseaseDoseEnzymesEthanolEventExposure toFibrosisFunctional disorderFutureHealthHeartHeart failureHeavy DrinkingHydrolysisHypertrophyImpairmentIn VitroIngestionInterventionInvestigational TherapiesLinkLipidsLiverLiver diseasesLuciferasesLysophosphatidic Acid ReceptorsLysophosphatidylcholinesMediatingMental disordersMessenger RNAMicroRNAsMitochondriaModelingMorbidity - disease rateMusMuscle CellsMutateMyocardialMyocardial dysfunctionMyocardiumNecrosisNeuraxisNormal tissue morphologyOxidation-ReductionOxidative StressPathway interactionsPlayProductionProtein DephosphorylationPublic HealthReactive Oxygen SpeciesRegulationReporterReportingRoleSignal TransductionSourceSuperoxide DismutaseTestingTranscriptional RegulationTranslationsUnited States National Institutes of Healthalcohol exposurecell typedesignextracellularheart damagein vivoinhibitor/antagonistinsightinterstitiallipid phosphate phosphataselysophosphatidic acidmanmimeticsmitochondrial dysfunctionmortalitynovelnuclear factors of activated T-cellsoffspringoxidant stressproblem drinkerpromoterprotective effectresponsetissue injurytranscription 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
项目成果
期刊论文数量(0)
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Manikandan Panchatcharam其他文献
Manikandan Panchatcharam的其他文献
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{{ truncateString('Manikandan Panchatcharam', 18)}}的其他基金
Oxidative stress mediated myocardial lipid dysfunction
氧化应激介导的心肌脂质功能障碍
- 批准号:
10331751 - 财政年份:2018
- 资助金额:
$ 20.99万 - 项目类别:
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