Heart Failure MicroRNA-24 Regulates Vascularity After Myocardial Infarction

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. M yocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. MI leads to scar formation and left ventricular remodeling, including cardiac dila-tation, contractile dysfunction, cardiomyocyte hypertrophy, and fibrosis. 1 Tissue hypoxia triggers endothelial apoptosis, and insufficient capillary density further contributes to an increase of infarct size and left ventricular dysfunction. 2– 4 Clinical Perspective on p 730 MicroRNAs (miRNAs) are endogenous small noncoding RNA molecules that regulate a substantial fraction of the genome by binding to the 3Ј untranslated region (3ЈUTR) of frequently coordinately acting target messenger RNAs. 5 MiRNAs have been identified as valuable therapeutic targets in a variety of diseases, including cardiovascular disease. 6 –12 Inhibition of miRNA processing by genetic knockdown of Dicer expression impairs endothelial functions and angiogen-esis. 13–15 Certain miRNAs are important regulators of endo-thelial function, especially angiogenesis. 7,13–17 A subset of miRNAs is regulated by tissue oxygen levels, and miR-24 is activated by hypoxic conditions via the hypoxia-inducible factor 1 (HIF-1). 18 Although miR-24 is expressed in a variety of organs, 19 it is enriched in endothelial cells, 20 but its role in the cardiovascular system remains basically uncertain. Here, we show that miR-24 acts as …