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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA014441-08
Application #
8494461
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Orosz, Andras
Project Start
2003-08-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
8
Fiscal Year
2013
Total Cost
$314,450
Indirect Cost
$95,321
Name
East Carolina University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
El-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2014) Endothelial and neuronal nitric oxide synthases variably modulate the oestrogen-mediated control of blood pressure and cardiovascular autonomic control. Clin Exp Pharmacol Physiol 41:246-54
El-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2014) Nongenomic effects of estrogen mediate the dose-related myocardial oxidative stress and dysfunction caused by acute ethanol in female rats. Am J Physiol Endocrinol Metab 306:E740-7
Taki, Faten A; Abdel-Rahman, Abdel A; Zhang, Baohong (2014) A comprehensive approach to identify reliable reference gene candidates to investigate the link between alcoholism and endocrinology in Sprague-Dawley rats. PLoS One 9:e94311
El-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2014) Ser/thr phosphatases tonically attenuate the ERK-dependent pressor effect of ethanol in the rostral ventrolateral medulla in normotensive rats. Brain Res 1577:21-8
Ibrahim, Badr M; Fan, Ming; Abdel-Rahman, Abdel A (2014) Oxidative stress and autonomic dysregulation contribute to the acute time-dependent myocardial depressant effect of ethanol in conscious female rats. Alcohol Clin Exp Res 38:1205-15
El-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2013) Cardiovascular autonomic modulation by nitric oxide synthases accounts for the augmented enalapril-evoked hypotension in ethanol-fed female rats. Alcohol 47:339-46
el-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2012) Exacerbation of myocardial dysfunction and autonomic imbalance contributes to the estrogen-dependent chronic hypotensive effect of ethanol in female rats. Eur J Pharmacol 679:95-100
El-Mas, Mahmoud M; Abdel-Rahman, Abdel A (2011) Bradykinin B2 receptor-dependent enhancement of enalapril-evoked hypotension in ethanol-fed female rats. J Cardiovasc Pharmacol 57:72-8
el-Mas, Mahmoud M; el-Gowilly, Sahar M; Gohar, Eman Y et al. (2011) Estrogen dependence of the renal vasodilatory effect of nicotine in rats: role of ýý7 nicotinic cholinergic receptor/eNOS signaling. Life Sci 88:187-93
El-Mas, Mahmoud M; Fan, Ming; Abdel-Rahman, Abdel A (2011) Upregulation of cardiac NOS due to endotoxemia and vagal overactivity contributes to the hypotensive effect of chronic ethanol in female rats. Eur J Pharmacol 650:317-23

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