Mechanisms For Estrogen-Dependent Myocardial Depressant Effect Of Ethanol

描述（由申请方提供）：与给予雄性动物心脏保护相反，急性乙醇导致雌性动物雌激素（E2）依赖性心肌抑制。尽管在上一个奖项期间取得了进展，但这种健康相关问题的分子机制仍未得到解决。我们假设E2介导的乙醇衍生的乙醛（ACA）的积累创造了有利于E2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-ALDH 2），因为E2增强其生理活性赋予心脏保护作用，这两种酶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-ALDH 2解毒ACA。我们推测，E2增强心肌过氧化氢酶活性可能会导致更高的乙醇衍生ACA。随后，较高ACA水平与更多细胞毒性底物对mit-ALDH 2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。为了验证我们的新假设，我们将采用多学科的方法，包括综合，细胞，分子和药理学研究，以解决以下具体目标。目的1研究非基因组快速ER信号通路增强介导乙醇诱导的氧化应激和雌性大鼠心肌抑制。目的2研究ACA生成酶（ADH、过氧化氢酶）和乙醛解毒酶（mit-ALDH 2）在乙醇引起的E2依赖性氧化应激和心肌抑制中的作用。目的3项研究将验证新的假设，即乙醇/ACA诱导的eNOS/nNOS解偶联在心肌和血管中E2向促炎激素的矛盾转化中起关键作用。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的靶点。 公共卫生相关性：鉴于年轻女性急性饮酒量的稳步上升，拟议的研究具有临床相关性，因为它：（i）阐明了雌激素如何将女性乙醇诱发的心脏保护转化为心脏抑制;（ii）确定酒精使用是临床研究中雌激素令人失望的结果的潜在贡献者;（iii）鉴定与女性中心脏保护酶心肌mit-ALDH 2的较高生理活性有关的雌激素受体亚型。

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. PUBLIC HEALTH RELEVANCE: Given the steady rise in acute alcohol consumption by young women, the proposed research is clinically relevant because it: (i) elucidates how estrogen transforms ethanol-evoked cardio-protection into cardiodepression in females; (ii) identifies alcohol use as potential contributor to the disappointing outcomes with estrogen in clinical studies; (iii) identifies the estrogen receptor subtype(s) implicated in the higher physiological activity of the cardioprotective enzyme, myocardial mit-ALDH2 in females.