title: Estrogen Receptors α and β Play Major Roles in Ethanol-Evoked Myocardial Oxidative Stress and Dysfunction in Conscious Ovariectomized Rats.
abstract: We documented the dependence of ethanol (EtOH)-evoked myocardial dysfunction on estrogen (E2), and our recent estrogen receptor (ER) blockade study, in proestrus rats, implicated ERα signaling in this phenomenon. However, a limitation of selective pharmacological loss-of-function approach is the potential contribution of the other 2 ERs to the observed effects because crosstalk exists between the 3 ERs. Here, we adopted a "regain"-of-function approach (using selective ER subtype agonists) to identify the ER subtype(s) required for unraveling the E2-dependent myocardial oxidative stress/dysfunction caused by EtOH in conscious ovariectomized (OVX) rats.
  
  
  
  OVX rats received a selective ERα (PPT), ERβ (DPN), or GPER (G1) agonist (10 μg/kg; i.v.) or vehicle 30 minutes before EtOH (1.0 g/kg; infused i.v. over 30 minutes) or saline, and the hemodynamic recording continued for additional 60 minutes. Thereafter, left ventricular tissue was collected for conducting ex vivo molecular/biochemical studies.
  
  
  
  EtOH had no hemodynamic effects in OVX rats, but reduced the left ventricular contractility index, dP/dtmax, and MAP after acute ERα (PPT) or ERβ (DPN) activation. These responses were associated with increases in the phosphorylation of ERK1/2 and eNOS, and in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in the myocardium. GPER activation (G1) only unraveled a modest EtOH-evoked hypotension and elevation in myocardial ROS. PPT enhanced catalase, DPN reduced ALDH2, while G1 had no effect on the activity of either enzyme, and none of the agonists influenced alcohol dehydrogenase or CYP2E1 activities in the myocardium. Blood EtOH concentration (96.0 mg/dl) was significantly reduced following ERα (59.8 mg/dl) or ERβ (62.9 mg/dl), but not GPER (100.3 mg/dl), activation in EtOH-treated OVX rats.
  
  
  
  ERα and ERβ play major roles in the E2-dependent myocardial dysfunction caused by EtOH by promoting combined accumulation of cardiotoxic (ROS and MDA) and cardiodepressant (NOS-derived NO) molecules in female myocardium.
authors.affiliation: Department of Pharmacology & Toxicology (FY, AAA-R), Brody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Fanrong
authors.initials: F
authors.lastname: Yao
authors.affiliation: Department of Pharmacology & Toxicology (FY, AAA-R), Brody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Abdel-Rahman
mesh_terms: D000818:Animals; D002492:Central Nervous System Depressants / Q000097:blood / Q000633:toxicity*; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000187:drug effects*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000187:drug effects*; D000431:Ethanol / Q000097:blood / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D018384:Oxidative Stress / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D002492:Central Nervous System Depressants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D017382:Reactive Oxygen Species; D000431:Ethanol; D008315:Malondialdehyde; D052250:Nitric Oxide Synthase Type III
keywords: Blood Pressure; Estrogen Receptors; Ethanol; Myocardial Function; Ovariectomized Rats; Oxidative Stress