Abstract 3: Il-10 Regulated Mir-375 Enhances Endothelial Progenitor Cell Mediated Myocardial Repair And Survival After Myocardial Infarction.

Abstract

We hypothesized that IL-10 regulates miR-375 signaling in EPCs to enhance their survival and function in ischemic myocardium after MI. miR-375 knock down EPC were transplanted intramyocardially after induction of MI. Mice receiving EPC treated with miR-375 inhibitor showed increased number of GFP+EPCs retention that was associated with reduced EPC apoptosis in the myocardium. The engraftment of EPC into the vascular structures and the associated capillary density was significantly higher in miR-375-treated mice. The above findings further correlated with reduced infarct size, fibrosis and enhanced LV function (echocardiography) in miR-375 knock down EPC group as compared to scrambled EPC. Our in vitro studies revealed that the knockdown of miR-375 enhanced EPC proliferation, migration; tube formation ability and inhibited cell apoptosis, while the up-regulation of miR-375 with the mimic had the opposite effects. In addition, we found that miR-375 negatively regulates the expression of 3-phosphoinositide-dependent protein kinase 1 (PDK1) by directly targeting the 3'UTR of the PDK1 transcript. Interestingly, EPC isolated from IL-10-deficient mice has elevated basal levels of miR-375 and exhibited poor proliferation and tube formation ability where as miR-375 knock down in EPC isolated from IL-10 deficient mice attenuated these effects. Furthermore, transplantation of miR-375 knock down IL-10 deficient EPC after MI resulted in attenuated cardiac functions compared to scramble IL-10 deficient EPCs. Taken together, our studies suggest that IL-10 regulated miR-375 enhances EPC survival and function, associated with efficient myocardial repair via activation of PDK-1/AKT signaling cascades.