Abstract 272: Epigenetic Regulation Involved in Diabetes-induced Impairment in Myocardial Reparative Function of Endothelial Progenitor Cell-derived Exosomes

Abstract

Myocardial infarction (MI) occurs frequently in patients with diabetes resulting in higher mortality and morbidity than non-diabetic patients. We and others have shown that bone marrow-derived endothelial progenitor cells (EPCs) promote cardiac neovascularization and attenuate ischemic injury in animal models. Moreover, emerging evidence supports that exosomes (Exo) mediate stem cell therapy by carrying cell-specific biological signatures and by inducing signaling via transfer of bioactive molecules to target cells. However, autologous cell-based therapies yielded modest clinical results, suggesting that cellular/Exo reparative function may be compromised on a background of disease such as diabetes. In addition, recent studies suggest epigenetic mechanisms, such as histone methylation for gene silencing, promotes diabetes-induced vascular complication. Therefore, we hypothesized that diabetic EPCs produce exosomes of altered and dysfunctional content which compromise EPC reparative function in ischemic heart disease via epigenetic alterations. We collected EPC-Exo from non-diabetic mice (Lepr db/+ ) and diabetic mice (Lepr db/db ) and examined their effect on tube formation and cardiomyocyte/endothelial cell survival in vitro as well as their reparative effects on permanent and acute ischemia/reperfusion (I/R) myocardial ischemic injuries in vivo . Diabetic EPC-Exo promoted neonatal rat cardiomyocyte cell apoptosis under hypoxic stress and repressed endothelial tube formation and cell survival compared to cells treated with WT EPC-Exo. In vivo studies revealed diabetic EPC-Exo significantly attenuated cardiac function, reduced capillary density, increased fibrosis and infarct size in permanent LAD ligation and I/R MI models. Mechanistically,H3K9Me3 was increased in mouse cardiac endothelial cells treated with diabetic EPC-exo, suggesting inhibition of angiogenic genes. Our results provide evidence that diabetic EPC-derived exosomes lose their cardiac reparative activities. Specific angiogenic genes will be examined by CHIP analysis of H3K9Me3. Reversing EPC-Exo function by manipulating H3K9Me3 expression will augment autologous therapies in regenerative medicine.