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*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

92 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 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.
Original languageEnglish
Pages (from-to)1390-1402
Number of pages13
JournalMolecular Therapy
Volume21
Issue number7
DOIs
Publication statusPublished - Jul 2013

Keywords

  • CARDIAC FIBROSIS
  • GROWTH-FACTOR
  • APOPTOSIS
  • TARGETS
  • CELLS
  • HEART
  • CARDIOGENESIS
  • DYSREGULATION
  • HYPERTROPHY
  • ISCHEMIA

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    Meloni, M., Marchetti, M., Garner, K., Littlejohns, B., Sala-Newby, G., Xenophontos, N., Floris, I., Suleiman, M. S., Madeddu, P., Caporali, A., & Emanueli, C. (2013). Local inhibition of microRNA-24 improves reparative angiogenesis and left ventricle remodeling and function in mice with myocardial infarction. Molecular Therapy, 21(7), 1390-1402. https://doi.org/10.1038/mt.2013.89