Research Article
Local Inhibition of MicroRNA-24 Improves Reparative Angiogenesis and Left Ventricle Remodeling and Function in Mice With Myocardial Infarction
Marco Meloni, Micol Marchetti, Kathryn Garner, Ben Littlejohns, Graciela Sala-Newby, Natasa Xenophontos, Ilaria Floris, M-Saadeh Suleiman, Paolo Madeddu, Andrea Caporali, Costanza Emanueli
Published:
July 01, 2013
DOI:
10.1038/mt.2013.89
License:
Copyright © 2013 The American Society of Gene & Cell Therapy2013The American Society of Gene & Cell TherapyThis work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
Abstract
Myocardial infarction (MI) is the leading cause of death worldwide. MicroRNAs regulate the expression of their target genes, thus mediating a plethora of pathophysiological functions. Recently, miRNA-24 emerged as an important but controversial miRNA involved in post-MI responses. Here, we aimed at clarifying the effect of adenovirus-mediate intra-myocardial delivery of a decoy for miRNA-24 in a mouse MI model and to investigate the impact of miRNA-24 inhibition on angiogenesis and cardiovascular apoptosis. After MI induction, miRNA-24 expression was lower in the peri-infarct tissue and its resident cardiomyocytes and fibroblasts; while it increased in endothelial cells (ECs). Local adenovirus-mediated miRNA-24 decoy delivery increased angiogenesis and blood perfusion in the peri-infarct myocardium, reduced infarct size, induced fibroblast apopotosis and overall improved cardiac function. Notwithstanding these beneficial effects, miRNA-24 decoy increased cardiomyocytes apoptosis. In vitro, miRNA-24 inhibition enhanced ECs survival, proliferation and networking in capillary-like tubes and induced cardiomyocyte and fibroblast apoptosis. Finally, we identified eNOS as a novel direct target of miR-24 in human cultured ECs and in vivo. Our findings suggest that miRNA-24 inhibition exerts distinct biological effects on ECs, cardiomyocytes and fibroblasts. The overall result of post-infarction local miRNA-24 inhibition appears to be therapeutic.