Estrogen modulation of the ethanol-evoked myocardial oxidative stress and dysfunction via DAPK3/Akt/ERK activation in male rats

Abstract

Evidence suggests that male rats are protected against the hypotensive and myocardial depressant effects of ethanol compared with females. We investigated whether E2 modifies the myocardial and oxidative effects of ethanol in male rats. Conscious male rats received ethanol (0.5, 1 or 1.5 g/kg i.v.) 30-min after E2 (1 μg/kg i.v.) or its vehicle (saline), and hearts were collected at the conclusion of hemodynamic measurements for ex vivo molecular studies. Ethanol had no effect in vehicle-treated rats, but it caused dose-related reductions in LV developed pressure (LVDP), end-diastolic pressure (LVEDP), rate of rise in LV pressure (dP/dtmax) and systolic (SBP) and diastolic (DBP) blood pressures in E2-pretreated rats. These effects were associated with elevated (i) indices of reactive oxygen species (ROS), (ii) malondialdehyde (MDA) protein adducts, and (iii) phosphorylated death-associated protein kinase-3 (DAPK3), Akt, and extracellular signal-regulated kinases (ERK1/2). Enhanced myocardial antioxidant enzymes (heme oxygenase-1, catalase and aldehyde dehydrogenase 2) activities were also demonstrated. In conclusion, E2 promotes ethanol-evoked myocardial oxidative stress and dysfunction in male rats. The present findings highlight the risk of developing myocardial dysfunction in men who consume alcohol while receiving E2 for specific medical conditions.

Estrogen receptor ERα plays a major role in ethanol-evoked myocardial oxidative stress and dysfunction in conscious female rats

“…4A). This new finding supports ERα mediation of the nongenomic E 2 enhancement of myocardial catalase activity in our recent study (El-Mas and Abdel-Rahman, 2015), and might explain the greatest increase in myocardial ROS following ERα, compared to ERβ or GPER, blockade (Fig. 6D).…”

“…The findings support our hypothesis that oxidative stress creates a cellular environment that transforms estrogen from being an antiinflammatory into a proinflammatory hormone. This notion is supported by the inability of ethanol to cause myocardial dysfunction, despite its induction of oxidative stress, unless endogenous or exogenous E 2 is present in female (El-Mas and Abdel-Rahman, 2014, Ibrahim et al, 2014) or male (El-Mas and Abdel-Rahman, 2015). Similarly, the E 2 -evoked coronary vasodilation is transformed into vasoconstriction in presence of oxidative stress (White et al, 2005).…”

“…The three ER subtypes, ERα, ERβ and the G protein-coupled estrogen receptor 1 (GPER) are distributed throughout the cardiovascular system, and act as important regulators of myocardial function by genomic and rapid non-genomic signaling mechanisms (Meyer et al, 2006, Meyer et al, 2011). Importantly, our recent findings that estrogen non-genomic effects are involved in ethanol-evoked myocardial depression and hypotension in female (El-Mas and Abdel-Rahman, 2014) and male (El-Mas and Abdel-Rahman, 2015) rats implicate one or more of the ER subtypes in the acute E 2 -dependent myocardial depressant effect of ethanol.…”

Influence of sex on cardiovascular drug responses: role of estrogen

“…These findings might explain, at least partly, the exacerbated deleterious cardiovascular consequences of diabetes in women (23*) because diabetes is associated with oxidative stress (28). This concept gains credence from our findings, which established a causal link between oxidative stress and estrogen-dependent deleterious cardiac effects in vivo because: (i) the alcohol-evoked myocardial oxidative stress is tolerated in the absence of estrogen in ovariectomized and male rats, and (ii) such resilience is lost, and is transformed into myocardial dysfunction, when estrogen is co-administered with ethanol in both sexes (6, 29**, 30). Current evidence implicates the ERα and ERβ subtypes in mediating these estrogen-dependent adverse cardiac effects of ethanol (27, 29**), at least partly, via the PI3K-Akt-NOS pathway (29**, 31, 32).…”

Etiology of alcoholic cardiomyopathy: Mitochondria, oxidative stress and apoptosis

“…In vivo studies examining ROS production after acute alcohol intoxication have also provided inconsistent results as ROS was increased at 10, 15, 20, 25 and 30 min after an acute bolus of alcohol (1 g/kg) in male rats (53), but not in a separate investigation that used similar doses and exposure times (0.5, 1, and 1.5 g/kg; 0–60 min) (54). The later study, however, established a role for sex hormones as estrogen (E2) administration to male rats prior to the alcohol bolus (1 g/kg and 1.5 g/kg) increased ROS (54) to match the increase normally observed in female rats (0.5 or 1.5 g/kg; 1 g/kg, intragastric) (55, 56).…”