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

Our previous studies showed that ethanol elicited estrogen (EA-dependent myocardial oxidative stress and dysfunction. In the present study we tested the hypothesis that E-2 signaling via the estrogen receptor (ER), ER alpha, mediates this myocardial detrimental effect of alcohol. To achieve this goal, conscious female rats in proestrus phase (highest endogenous E-2 level) received a selective ER antagonist (200 mu g/kg; intra-venous [i.v.]) for ER alpha (MPP), ER beta (PHTPP) or GPER (G15) or saline 30 min before ethanol (1 g/kg; i.v.) or saline infusion. ERa blockade virtually abrogated ethanol-evoked myocardial dysfunction and hypotension, while ER beta blockade had little effect on the hypotensive response, but caused delayed attenuation of the ethanol-evoked reductions in left ventricular developed pressure and the rate of left ventricle pressure rise. GPER blockade caused delayed attenuation of all cardiovascular effects of ethanol. All three antagonists attenuated the ethanol-evoked increases in myocardial catalase and ALDH2 activities, Akt, ERK1/2, p38, eNOS, and nNOS phosphorylation, except for a lack of effect of PHTPP on p38. Finally, all three ER antagonists attenuated ethanol-evoked elevation in myocardial ROS, but this effect was most notable with ER alpha blockade. In conclusion, ERa plays a greater role in, and might serve as a molecular target for ameliorating, the E-2-dependent myocardial oxidative stress and dysfunction caused by ethanol. (C) 2016 Elsevier Inc. All rights reserved.