title: Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction.
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.
authors.affiliation: Laboratory of Vascular Pathology and Regeneration, School of Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Meloni
authors.forename: Micol
authors.initials: M
authors.lastname: Marchetti
authors.forename: Kathryn
authors.initials: K
authors.lastname: Garner
authors.forename: Ben
authors.initials: B
authors.lastname: Littlejohns
authors.forename: Graciela
authors.initials: G
authors.lastname: Sala-Newby
authors.forename: Natasa
authors.initials: N
authors.lastname: Xenophontos
authors.forename: Ilaria
authors.initials: I
authors.lastname: Floris
authors.forename: M-Saadeh
authors.initials: MS
authors.lastname: Suleiman
authors.forename: Paolo
authors.initials: P
authors.lastname: Madeddu
authors.forename: Andrea
authors.initials: A
authors.lastname: Caporali
authors.forename: Costanza
authors.initials: C
authors.lastname: Emanueli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D035683:MicroRNAs; C529080:Mirn24 microRNA, mouse; D052250:Nitric Oxide Synthase Type III