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MicroRNA-24 regulates vascularity after myocardial infarction

Fiedler, J. and Jazbutyte, V. and Kirchmaier, B. C. and Gupta, S. K. and Lorenzen, J. and Hartmann, D. and Galuppo, P. and Kneitz, S. and Pena, J. and Sohn-Lee, C. and Loyer, X. and Soutschek, J. and Brand, T. and Tuschl, T. and Heineke, J. and Martin, U. and Schulte-Merker, S. and Ertl, G. and Engelhardt, S. and Bauersachs, J. and Thum, T. (2011) MicroRNA-24 regulates vascularity after myocardial infarction. Circulation, 124, 720-30. ISSN 0009-7322.

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Official URL: http://dx.doi.org/10.1161/circulationaha.111.039008

Abstract

BACKGROUND: Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood. METHODS AND RESULTS: Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia. MiR-24 induces endothelial cell apoptosis, abolishes endothelial capillary network formation on Matrigel, and inhibits cell sprouting from endothelial spheroids. These effects are mediated through targeting of the endothelium-enriched transcription factor GATA2 and the p21-activated kinase PAK4, which were identified by bioinformatic predictions and validated by luciferase gene reporter assays. Respective downstream signaling cascades involving phosphorylated BAD (Bcl-XL/Bcl-2-associated death promoter) and Sirtuin1 were identified by transcriptome, protein arrays, and chromatin immunoprecipitation analyses. Overexpression of miR-24 or silencing of its targets significantly impaired angiogenesis in zebrafish embryos. Blocking of endothelial miR-24 limited myocardial infarct size of mice via prevention of endothelial apoptosis and enhancement of vascularity, which led to preserved cardiac function and survival. CONCLUSIONS: Our findings indicate that miR-24 acts as a critical regulator of endothelial cell apoptosis and angiogenesis and is suitable for therapeutic intervention in the setting of ischemic heart disease. [KEYWORDS: Animals, Apoptosis/drug effects, Arterioles/pathology, Capillaries/pathology, Cell Hypoxia, Cells, Cultured/drug effects/metabolism, Collagen, Drug Combinations, Drug Evaluation, Preclinical, Endothelial Cells/ metabolism/pathology, GATA2 Transcription Factor/biosynthesis/genetics, Gene Expression Profiling, Heart Failure/etiology, Heme Oxygenase-1/biosynthesis/genetics, Laminin, Male, Mice, Mice, Inbred C57BL, MicroRNAs/antagonists & inhibitors/genetics/ physiology, Myocardial Infarc

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:12618
Deposited On:07 Sep 2012 16:55
Last Modified:19 Sep 2012 16:37

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