Abstract 16220: Negative Regulation of Mir-375 by Interleukin-10 Enhances Endothelial Progenitor Cell Mediated Myocardial Repair and Function After Myocardial Infarction
Despite some encouraging data, the bone marrow progenitor cells (BMPC) mediated clinical trials have only shown a very modest improvement in heart functions. Poor survival and function of transplanted cell in the ischemic and inflamed myocardium likely compromises the full functional benefit of stem cell based therapies. We have earlier reported that co-administration of IL-10 and BMPC not only enhances cell survival but also improved left ventricular (LV) functions after AMI in mice. We identified that microRNA-375 expression is significantly up-regulated in EPCs upon exposure to either inflammatory or hypoxic stimulus. 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 EPC 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 antagomir-treated mice. The above findings further correlated with reduced infarct size; fibrosis and enhanced LV function 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, tube formation ability and inhibited cell apoptosis. In addition, we found that miR-375 directly targets 3'UTR of the 3-phosphoinositide-dependent protein kinase 1 (PDK1) transcript. Interestingly, EPC isolated from IL-10-deficient mice showed elevated basal levels of miR-375 and exhibited poor proliferation and tube formation ability where as miR-375 knock down in IL-10 deficient EPCs partially rescued their phenotype. Furthermore, transplantation of miR-375 knock down IL-10 deficient EPC after MI resulted in better LV functions compared to untreated IL-10 deficient EPCs. Taken together, our studies suggest that miR 375 is negatively associated with EPC function and survival and IL-10-mediated repression of miR-375 enhances EPC survival and function, associated with efficient myocardial repair via activation of PDK-1/AKT signaling cascades.
Author Disclosures: V.N. Garikipati: None. P. Krishnamurthy: None. S.K. Verma: None. A. Mackie: None. M. Khan: None. J. Zhou: None. E. Vaughan: None. B. Arnone: None. T. Abramowa: None. V. Ramirez: None. A. klingler: None. K. Ellingson: None. S. Misener: None. C. Benedict: None. E. Nickoloff: None. J. Johnson: None. G. Qin: None. W.J. Koch: None. R. Kishore: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.