title: 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; intra-venous [i.v.]) for ERα (MPP), ERβ (PHTPP) or GPER (G15) or saline 30 min before ethanol (1 g/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.
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Fanrong
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC, USA. Electronic address: abdelrahmana@ecu.edu.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002374:Catalase / Q000378:metabolism; D003243:Consciousness; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors; D000431:Ethanol / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000097:blood; D005260:Female; D009206:Myocardium / Q000378:metabolism*; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: C524478:1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-(2-piperidinylethoxy)phenol)-1H-pyrazole; C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; C568862:4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline; D052117:Benzodioxoles; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; C520305:Gper1 protein, rat; D009566:Nitrates; D009573:Nitrites; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011804:Quinolines; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D000431:Ethanol; D002374:Catalase; D000444:Aldehyde Dehydrogenase
keywords: Blood pressure; Estrogen receptor subtypes; Ethanol; Myocardial function; Oxidative stress