Mechanisms For Estrogen-Dependent Myocardial Depressant Effect Of Ethanol

乙醇雌激素依赖性心肌抑制作用的机制

• 批准号: 8693868
• 负责人: ABDEL A ABDEL-RAHMAN
• 金额: $ 32.77万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8693868
• 关键词: Acetaldehyde; Acute; Address; Agonist; Alcohol consumption; Alcohols; Aldehydes; Animals; Award; Calmodulin; Cardiac Myocytes; Cardiovascular system; Cell surface; Clinical Research; Dose; Environment; Enzymes; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Ethanol; Ethanol dependence; Event; Female; Generations; Health; Heart; Hormones; Hyperactive behavior; Inflammatory; Intervention; Knockout Mice; MAPK3 gene; Mediating; Mediator of activation protein; Mental Depression; Mitochondria; Molecular; Myocardial; Myocardial Depressants; Myocardial dysfunction; Myocardium; NADPH Oxidase; Outcome; Oxidative Stress; Phosphorylation; Physiological; Play; Prevention; Rattus; Reactive Oxygen Species; Receptor Signaling; Reporting; Research; Role; Signal Transduction; Testing; Tissues; alcohol effect; aldehyde dehydrogenases; base; cardiac depression; catalase; caveolin-3; clinically relevant; cytotoxic; hemodynamics; interdisciplinary approach; male; non-genomic; novel; novel therapeutics; oxidation; response; tetrahydrobiopterin; young woman

DESCRIPTION (provided by applicant): Contrary to conferring cardioprotection in male animals, acute ethanol causes estrogen (E2)-dependent myocardial depression in females. Despite progress made during the previous award, the molecular mechanisms for this health related problem remain unresolved. We hypothesize that E2-mediated accumulation of ethanol-derived acetaldehyde (ACA) creates environment conducive to paradoxical transformation of E2 into a pro-inflammatory hormone. We will focus on myocardial catalase and mitochondrial aldehyde dehydrogenase 2 (mit-ALDH2) because E2 enhancement of their physiological activity confers cardioprotection and both enzymes regulate myocardial ethanol-derived ACA balance; catalase catalyzes ethanol oxidation to ACA and mit-ALDH2 detoxifies ACA. We hypothesize that E2 enhancement of myocardial catalase activity could result in higher ethanol-derived ACA. Subsequently, competition of higher ACA level with more cytotoxic substrates for mit-ALDH2 leads to accumulation of cytotoxic aldehydes (oxidative stress and myocardial dysfunction). We further hypothesize that E2 mediates these cellular effects via nongenomic estrogen receptor (ER) signaling. To test our novel hypotheses, we will employ a multidisciplinary approach that encompasses integrative, cellular, molecular and pharmacological studies to address the following specific aims. Aim 1 studies will test the hypothesis that enhancement of nongenomic rapid ER signaling mediates ethanol-evoked oxidative stress and myocardial depression in female rats. Aim 2 studies will elucidate the role of ACA generating (ADH, catalase) and aldehyde detoxifying (mit-ALDH2) enzymes in the E2-dependent oxidative stress and myocardial depression caused by ethanol. Aim 3 studies will test the novel hypothesis that ethanol/ACA- evoked eNOS/nNOS uncoupling plays pivotal role in the paradoxical transformation of E2 into proinflammatory hormone in the myocardium and vasculature. These studies will further our understanding of the molecular mechanisms for the E2-dependent myocardial dysfunction caused by acute alcohol and will allow identification of novel targets for new interventions for the treatment/prevention of cardiovascular anomalies caused by alcohol in females.

描述（由申请人提供）：与赋予雄性动物心脏保护作用相反，急性乙醇会导致雌性动物雌激素（E2）依赖性心肌抑制。尽管在上一奖项期间取得了进展，但这一健康相关问题的分子机制仍未得到解决。我们假设 E2 介导的乙醇衍生乙醛 (ACA) 的积累创造了有利于 E2 反常转化为促炎激素的环境。我们将重点关注心肌过氧化氢酶和线粒体醛脱氢酶 2 (mit-ALDH2)，因为 E2 增强其生理活性可实现心脏保护作用，并且这两种酶可调节心肌乙醇衍生的 ACA 平衡；过氧化氢酶催化乙醇氧化为 ACA，mit-ALDH2 使 ACA 解毒。我们假设 E2 增强心肌过氧化氢酶活性可能导致更高的乙醇衍生 ACA。随后，较高水平的 ACA 与更多细胞毒性底物 mit-ALDH2 的竞争导致细胞毒性醛的积累（氧化应激和心肌功能障碍）。我们进一步假设 E2 通过非基因组雌激素受体 (ER) 信号传导介导这些细胞效应。为了检验我们的新假设，我们将采用涵盖综合、细胞、分子和药理学研究的多学科方法来解决以下具体目标。目标 1 研究将检验以下假设：非基因组快速 ER 信号传导的增强介导雌性大鼠中乙醇引起的氧化应激和心肌抑制。目标 2 研究将阐明 ACA 生成酶（ADH、过氧化氢酶）和醛解毒酶（mit-ALDH2）在乙醇引起的 E2 依赖性氧化应激和心肌抑制中的作用。目标 3 研究将检验新的假设，即乙醇/ACA 引起的 eNOS/nNOS 解偶联在心肌和脉管系统中 E2 向促炎激素的矛盾转化中发挥着关键作用。这些研究将进一步加深我们对急性酒精引起的 E2 依赖性心肌功能障碍的分子机制的理解，并将为治疗/预防女性酒精引起的心血管异常的新干预措施确定新靶点。