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

Abstract

Our previous studies showed that ethanol elicited estrogen (E2)-dependent myocardial oxidative stress and dysfunction. In the present study we tested the hypothesis that E2 signaling via the estrogen receptor (ER), ERα, mediates this myocardial detrimental effect of alcohol. To achieve this goal, conscious female rats in proestrus phase (highest endogenous E2 level) received a selective ER antagonist (200 μg/kg; i.v) for ERα (MPP), ERβ (PHTPP) or GPER (G15) or saline 30 min before ethanol (1g/kg; i.v) or saline infusion. ERα blockade virtually abrogated ethanol-evoked myocardial dysfunction and hypotension, while ERβ 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 ERα blockade. In conclusion, ERα plays a greater role in, and might serve as a molecular target for ameliorating, the E2 dependent myocardial oxidative stress and dysfunction caused by 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).…”

Estrogen receptor α activation enhances its cell surface localization and improves myocardial redox status in ovariectomized rats

“…Further, we showed that acute ERα blockade by its selective antagonist MPP significantly reduced myocardial catalase activity in proestrus rats [40]. Collectively, these pharmacological findings support ERα mediation of cardiac catalase activation by acute or circulating E 2 .…”

“…TBARS Assay Kit (Cayman Chemical, Ann Arbor, MI, USA) was used to measure myocardial MDA level following the manufacturer’s protocol and the method descripted in our publication [40]. The MDA-TBA adduct was detected colorimetrically at 530–540 nm.…”

Estrogen Receptors α and β Play Major Roles in Ethanol‐Evoked Myocardial Oxidative Stress and Dysfunction in Conscious Ovariectomized Rats

“…Vascular and left ventricular catheterizations were performed as detailed in our recent study (Yao and Abdel‐Rahman, ). Briefly, gas‐sterilized arterial and venous catheters (Konigsberg Instruments Inc., Pasadena, CA), filled with heparinized saline, were placed into the abdominal aorta and vena cava via the femoral artery/vein for monitoring BP and for the administration of EtOH and/or the pharmacological intervention, respectively.…”

“…These findings, which are reminiscent of E 2 ‐dependent cardiovascular deficits following chronic EtOH administration (El‐Mas and Abdel‐Rahman, ), might be clinically relevant because EtOH reduces blood pressure (BP) in young, but not in older, women or men (Bae et al., ; Klatsky et al., ). Our recent study identified a pivotal role for the estrogen receptor (ER) subtype ERα in the E 2 ‐dependent myocardial dysfunction caused by EtOH (Yao and Abdel‐Rahman, ). However, the use of selective ER blockade in proestrus rats (highest level of endogenous E 2 ) in the latter study or the use of genetic ER‐knockout models (Sharma and Prossnitz, ) might confound data interpretation because a functional crosstalk exists between the 3 ERs (Shi et al., ).…”