miR-133a Enhances the Protective Capacity of Cardiac Progenitors Cells after Myocardial Infarction

miR-133a and miR-1 are known as muscle-specific microRNAs that are involved in cardiac development and pathophysiology. We have shown that both miR-1 and miR-133a are early and progressively upregulated during in vitro cardiac differentiation of adult cardiac progenitor cells (CPCs), but only miR-133a expression was enhanced under in vitro oxidative stress. miR-1 was demonstrated to favor differentiation of CPCs, whereas miR-133a overexpression protected CPCs against cell death, targeting, among others, the proapoptotic genes Bim and Bmf. miR-133a-CPCs clearly improved cardiac function in a rat myocardial infarction model by reducing fibrosis and hypertrophy and increasing vascularization and cardiomyocyte proliferation. The beneficial effects of miR-133a-CPCs seem to correlate with the upregulated expression of several relevant paracrine factors and the plausible cooperative secretion of miR-133a via exosomal transport. Finally, an in vitro heart muscle model confirmed the antiapoptotic effects of miR-133a-CPCs, favoring the structuration and contractile functionality of the artificial tissue.This work was supported by grants to A.B. from the Ministry of Economy and Competition (SAF2012-3432, PLE2009-0147, and PSE-010000-2009-3), the Comunidad Autonoma de Madrid (S2011/BMD-2420), ISCIII (RD12/0019/0018). W.-H.Z. is supported by the DZHK (German Center for Cardiovascular Research), the German Federal Ministry for Science and Education (BMBF FKZ 13GW0007A, joint program with the California Institute of Renerative Medicine), the German Research Foundation (DFG ZI 708/7-1, 8-1, 10-1, SFB 1002 TP C04 and TP S), and the NIH (U01 HL099997). A.B. and W.-H.Z. have been both supported by the European Commission (FP7-HEALTH-2009/CARE-MI). A.I. and I. M. were postdoctoral fellows funded by the Ministry of Economy and Competition. S.C. is a contracted scientist funded by ISCIII. The CNIC and CNB are supported by the Ministry of Economy and Competition. We thank Iria Sanchez, Tamara Cordoba, Erica Lopez, and Carmen Albo for technical help, Candelas Carreiro for logistics support, Marta Ramon for secretarial assistance, and Kenneth McCreath for help with manuscript editing.S