Abstract 11060: MicroRNA-377 Modulates Angiogenic Properties of Intramyocardially Transplanted Bone Marrow-Derived Progenitor Cells After Myocardial Infarction
MicroRNAs (miRNA/miR) dysregulation has been implicated in cardiac remodeling after injury or stress, however its effects on endothelial progenitor cells (EPC) biology and function, particularly in the context of cell-based therapy for cardiomyopathy is not fully understood. The purpose of this study was to determine the miRNA profile of EPCs in response to chronic inflammatory stimuli and evaluate if miRNA-377 impairs differentiation and function of bone marrow-derived EPCs, after transplantation in myocardial ischemic conditions. miRNA array profile of EPCs in response to inflammatory stimuli (LPS, 50ng/ml) for 12 hrs, EPC migration and invitro vascular tube formation was analyzed. GFP-labeled EPC (transfected with either anti-miR-377 or control-anti-miR) were transplanted intramyocardially after induction of MI. EPC-mediated neovascularization, left ventricular function and myocardial repair was evaluated at 14 and 28 days, post-MI. miRNA array data from EPCs in response to inflammatory stimuli has indicated up-regulation of number of miRNAs related to cell survival/death and angiogenesis with a robust increase in miR-377. pre-miR-377 (miRNA mimics) transfection in EPCs inhibits their migration (modified Boyden chamber, P<0.05) and vascular tube formation ability (matrigel assay, P<0.05). Furthermore, EPCs treated with miR-377 mimic showed decrease in protein expression of STK35 (a novel serine/threonine kinase localized in the nucleus). Moreover, STK35 is predicted as a potential target gene of miR-377 by computational analysis. Interestingly, in a relevant mouse model of myocardial infarction (MI), intramyocardial transplantation of miR-377-silenced (anti-miR-377 transfected, GFP-labeled) EPCs promotes neovascularization (at 28 days, post-MI) leading to improvement in myocardial repair (reduced fibrosis and infarct size). Echocardiography showed LV function was significantly improved in mice receiving miR-377-silenced EPCs compared to control-miR-transfected EPCs. Taken together, these data suggest that inhibiting miR-377 in EPCs might promote their engraftment and angiogenic ability after transplantation into ischemic myocardial tissue, possibly through activation of STK35 signaling axes.
Author Disclosures: D. Joladarashi: None. R.A. Thandavarayan: None. S.S. Babu: None. G.V. Srikanth: None. S.K. Verma: None. A.R. Mackie: None. M. Khan: None. E.E. Vaughan: None. R. Kishore: None. P. Krishnamurthy: None.
- © 2014 by American Heart Association, Inc.