Estrogen Receptors Alpha And Beta Play Major Roles In Ethanol-Evoked Myocardial Oxidative Stress And Dysfunction In Conscious Ovariectomized Rats

Background: We documented the dependence of ethanol (EtOH)-evoked myocardial dysfunction on estrogen (E-2), and our recent estrogen receptor (ER) blockade study, in proestrus rats, implicated ER alpha 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 E-2-dependent myocardial oxidative stress/dysfunction caused by EtOH in conscious ovariectomized (OVX) rats.Methods: OVX rats received a selective ERa (PPT), ERb (DPN), or GPER (G1) agonist (10 mu g/kg; i.v.) or vehicle 30 minutes before EtOH (1.0 g/kg; infused i.v. over 30 minutes) or saline, and the hemo-dynamic recording continued for additional 60 minutes. Thereafter, left ventricular tissue was collected for conducting ex vivo molecular/biochemical studies.Results: EtOH had no hemodynamic effects in OVX rats, but reduced the left ventricular contractility index, dP/dt(max), and MAP after acute ER alpha (PPT) or ER beta (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 ER alpha (59.8 mg/dl) or ER beta (62.9 mg/dl), but not GPER (100.3 mg/dl), activation in EtOH-treated OVX rats.Conclusions: ER alpha and ER beta 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.