Mechanisms For Estrogen-Dependent Myocardial Depressant Effect Of Ethanol Grant uri icon

abstract

  • While acute ethanol (in male animals) or estrogen (E2) elicits cardioprotection, their combination causes myocardial depression in female rats. Despite progress made during the previous award, the molecular mechanisms for this 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 aldehyde dehydrogenase 2 (ALDH2) because they mediate E2 cardioprotection and regulate myocardial ethanol-derived ACA balance. First, in presence of E2, higher catalytic activity of myocardial catalase could result in higher ethanol-derived ACA and other cytotoxic aldehydes. Second, ability of mitochondrial ALDH2 to detoxify these cytotoxic aldehydes (reported in male rats) might be limited because of higher basal ALDH2 activity in female rats. Subsequently, accumulated cytotoxic aldehydes will induce oxidative stress and cause 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, signal transduction and pharmacological studies to address the following inter-related specific aims. Aim 1 studies will test the hypothesis that enhancement of nongenomic rapid ER-alpha 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 (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 uncoupling creates a microenvironment conducive to paradoxical transformation of E2 into proinflammatory hormone in the myocardium and vasculature. These studies should further our understanding of the molecular mechanisms implicated in the E2-dependent myocardial dysfunction caused by acute alcohol consumption and will allow identification of novel targets for new interventions for the treatment/prevention of cardiovascular anomalies caused by alcohol in females.

date/time interval

  • April 2010 - February 2018