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Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction

Meloni, Marco and Marchetti, Micol and Garner, Kathryn and Littlejohns, Ben and Sala-Newby, Graciela and Xenophontos, Natasa and Floris, Ilaria and Suleiman, M-Saadeh and Madeddu, Paolo Roberto and Caporali, Andrea and Emanueli, Costanza (2013) Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction. Molecular Therapy, Vol. 21 (7), p. 1390-1402. eISSN 1525-0024. Article.

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DOI: 10.1038/mt.2013.89

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.

Item Type:Article
ID Code:9649
Status:Published
Refereed:Yes
Uncontrolled Keywords:Myocardial infarction (MI), MicroRNA-24, angiogenesis, cardiovascular apoptosis
Subjects:Area 05 - Scienze biologiche > BIO/10 Biochimica
Divisions:001 Università di Sassari > 01-a Nuovi Dipartimenti dal 2012 > Scienze Biomediche
Publisher:Nature Publishing Group
eISSN:1525-0024
Copyright Holders:© the American Society of Gene and cell therapy
Additional Information:The study was supported by a grant from Diabetes UK and the British Heart Foundation (BHF). I.F. is supported by a PhD studentship bursary from the University of Sassari Italy.
Deposited On:27 Feb 2014 10:11

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