Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodelling 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

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101 Citations (Scopus)

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 postMI 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 capillarylike 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
Original languageEnglish
Pages (from-to)1390-1402
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume21
Issue number7
Publication statusPublished - 18 Jun 2013
Externally publishedYes

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