Abstract 180: Alcohol Consumption Negatively Competes with Estrogen-Mediated Myocardial Repair in Ovariectomized Mice: Ethanol-Mediated Suppression of Estradiol-Induced Survival Signaling in Endothelial Progenitor Cells
Studies in post-menopausal women and ovariectomized (OVX) animals have suggested a cardio-protective (CP) role of estrogen replacement therapy. However, randomized clinical trials have not confirmed this finding with hormone replacement (HRT). Although HRT initiation and duration might explain part of this disparity, other factors that mask the CP effect of estradiol (E2) require scrutiny. We and others have reported that E2-supplementation (E2sup) with 17β-E2 pellets enhances voluntary alcohol consumption in OVX mice. In this study, we examined the effect that enhanced ethanol consumption with E2sup has on post-infarct myocardial function and repair. E2sup OVX BALB/c mice, consumed significantly more 10% ethanol for 6 weeks compared to those implanted with placebo pellets. Following acute myocardial infarction (AMI), LV functions were consistently depressed in mice consuming ethanol (E2sup+Etoh) compared to mice receiving only E2sup. Additionally, the E2sup+Etoh group also displayed a loss of the improvements in both fibrosis area and capillary density observed in the E2sup mice following AMI. E2sup+Etoh mice also displayed a diminished number of circulating endothelial progenitor cells (EPCs) as compared to the E2sup group. In vitro, exposure of EPCs to ethanol suppressed E2-induced EPC proliferation and survival. At the molecular level, estrogen response element (ERE) DNA binding activity and ERE-dependent reporter gene transcription were markedly repressed in ethanol treated EPCs. Ethanol also attenuated E2-induced eNOS expression and phosphorylation. Furthermore, ethanol blocked E2-induced activation of cell survival signaling pathways, Akt and ERK, and activated the pro-apoptotic JNK signaling via direct association with mixed lineage kinase 3. These data suggest that E2 modulation of alcohol consumption and the ensuing EC dysfunction may negatively compete with the beneficial effects of estrogen on the heart.
- © 2012 by American Heart Association, Inc.