Animal studies have established that estrogen (E2) is a known cardio-protective hormone that helps recruit bone-marrow derived endothelial progenitor/stem cells (EPC) in the injured heart which, in turn, participate in the vascular repair of injured tissue. We and others have shown that E2-supplementation enhances the consumption of ethanol in ovariectomized (OVX) mice. However, whether alcohol/estrogen interactions alter the biology of EPCs or whether change in the microenvironment (alcohol) competes with the known beneficial effects of E2 on EPC-mediated myocardial repair is not known. The premise of our proposed research is based on our following published and preliminary observations: a) OVX mice receiving E2 (17b-estradiol) supplementation consume significantly more ethanol compared to those receiving placebo;b) E2-mediated re-endothelialization in denuded carotid arteries and E2-mediated neo-vascularization and blood flow recovery in ischemic hind limbs is blunted in mice consuming ethanol, despite E2 supplementation;c) in a mouse model of acute myocardial infarction (AMI) increased ethanol consumption following E2-supplementation reduces EPC mobilization and homing to ischemic tissues in eNOS and MMP9 dependent manner, depresses physiological and anatomical tissue repair and represses neo-vasculogenesis;d) in vitro, ethanol dose-dependently attenuates E2-induced proliferation, tubulogenesis and survival of both EPCs and mature endothelial cells (EC);interferes with genomic and non-genomic functions of estrogen receptors and switches the E2-mediated cell survival signaling to the induction of pro-apoptotic signaling. Our central hypothesis, therefore, is that increased ethanol consumption competes with E2-mediated post-infarct myocardial repair by negating the protective effects of E2 on EPC function and signaling. The experiments described in the current proposal are designed to extend these findings by testing a series of hypotheses grouped according to the following 3 specific aims: 1) Determine the role of individual estrogen receptors (ER) on ethanol-mediated repression of BM-EPC mobilization and post-AMI myocardial repair, 2) Define the role of eNOS and MMP9 in ethanol repression of E2-induced BM-EPC mobilization and function in post-AMI myocardial repair and 3) Elucidate molecular signaling involved in the ethanol-mediated suppression of E2-induced cell survival signaling pathways in EPC.
Certain diseases like myocardial infarction (MI) are the major cause of mortality in post- menopausal women. Estrogen is a known cardio-protective hormone helps recruit bone-marrow derived endothelial progenitor/stem cells (EPC) in the injured heart for injured tissue repair. However, estrogen therapy also increases alcohol consumption which may compete with the benefits provided by estrogen on progenitor cells. This proposal will test mechanisms by which alcohol consumption may mask the cardio-protective effects of estrogen, specifically as estrogen/alcohol interactions may affect the biology of EPC during experimental heart injury.
|Tongers, Jörn; Webber, Matthew J; Vaughan, Erin E et al. (2014) Enhanced potency of cell-based therapy for ischemic tissue repair using an injectable bioactive epitope presenting nanofiber support matrix. J Mol Cell Cardiol 74:231-9|
|Kishore, Raj; Verma, Suresh K; Mackie, Alexander R et al. (2013) Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts. PLoS One 8:e60161|
|Ghosh, Asish K; Murphy, Sheila B; Kishore, Raj et al. (2013) Global gene expression profiling in PAI-1 knockout murine heart and kidney: molecular basis of cardiac-selective fibrosis. PLoS One 8:e63825|
|Mackie, Alexander R; Krishnamurthy, Prasanna; Verma, Suresh K et al. (2013) Alcohol consumption negates estrogen-mediated myocardial repair in ovariectomized mice by inhibiting endothelial progenitor cell mobilization and function. J Biol Chem 288:18022-34|
|Zhou, Junlan; Cheng, Min; Wu, Min et al. (2013) Contrasting roles of E2F2 and E2F3 in endothelial cell growth and ischemic angiogenesis. J Mol Cell Cardiol 60:68-71|
|Krishnamurthy, Prasanna; Thal, Melissa; Verma, Suresh et al. (2011) Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium. Circ Res 109:1280-9|