title: Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function.
abstract: We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17β-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair.
authors: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors: Alexander R
authors: AR
authors: Mackie
authors: Prasanna
authors: P
authors: Krishnamurthy
authors: Suresh K
authors: SK
authors: Verma
authors: Tina
authors: T
authors: Thorne
authors: Veronica
authors: V
authors: Ramirez
authors: Gangjian
authors: G
authors: Qin
authors: Tatiana
authors: T
authors: Abramova
authors: Hiromichi
authors: H
authors: Hamada
authors: Douglas W
authors: DW
authors: Losordo
authors: Raj
authors: R
authors: Kishore
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics; D010052:Ovariectomy; D011485:Protein Binding / Q000187:drug effects; D011960:Receptors, Estrogen / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology
chemical_list: D004967:Estrogens; D011960:Receptors, Estrogen; D000431:Ethanol; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: Alcohol; Cardiovascular; Estrogen; Ischemia; Signal Transduction
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