MicroRNA-24 Regulates Vascularity After Myocardial Infarction

Article

关键词: HUMAN ENDOTHELIAL-CELLS;    HEART-FAILURE;    GENE-EXPRESSION;    CONTROLS ANGIOGENESIS;    CARDIAC-HYPERTROPHY;    DOWN-REGULATION;    KAPPA-B;    ACTIVATION;    NEOVASCULARIZATION;    ZEBRAFISH;   

DOI  :  10.1161/CIRCULATIONAHA.111.039008

来源: SCIE

【 摘 要 】

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. (Circulation. 2011; 124: 720-730.)

【 授权许可】

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