MicroRNA-24 Regulates Vascularity After Myocardial Infarction

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 angiogenesisand is suitable for therapeutic intervention in the setting of ischemic heart disease. (Circulation. 2011;124:720-730.)Key Words: myocardial infarction Ⅲ microRNAs Ⅲ angiogenesis Ⅲ antagomir Ⅲ gene expression Ⅲ heart failure M yocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. MI leads to scar formation and left ventricular remodeling, including cardiac dilatation, 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][3][4] Clinical Perspective on p 730MicroRNAs (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 angiogenesis. [13][14][15] Certain miRNAs are important regulators of endothelial 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 Received April 19, 2011; accepted June 7, 2011 Table I). The small RNA...

SON Protein Regulates GATA-2 through Transcriptional Control of the MicroRNA 23a∼27a∼24-2 Cluster*

“…In zebrafish, miR-451 targets gata-2 during erythroid maturation (31). miR-24 was also shown to target GATA-2 in human endothelial cells (32). Although we observed that miR-24 is up-regulated upon SON knockdown in both K562 cells and EML cells, overexpression of miR-24 did not target the 3Ј-UTR of GATA-2 in hematopoietic cells (Fig.…”

miRNAs and lncRNAs in vascular injury and remodeling

“…Many of these miRNAs inhibit angiogenesis by suppressing proliferation and migration of endothelial cells, such as miR-21 by targeting proliferators-activated receptor-alpha (PPAR-α) and RhoB [27]; miR-200b by down-regulating Ets-1, VEGF, VEGFR-2 and GATA2 [28]; miR-92a by suppressing integrin subunit a5 [29]; and miR-221/222 by negatively regulating the expression of c-kit [30]. Moreover, in addition to suppressing angiogenesis by regulating GATA2, miR-24 also induces apoptosis by targeting p21-activating kinase 4 (PAK4) [31]. Similarly, miR-34a is significant in promoting senescence of endothelial cells, while it impedes angiogenesis by suppressing SIRT1 [32].…”

miRNA-30 Family Inhibition Protects Against Cardiac Ischemic Injury by Regulating Cystathionine-γ-Lyase Expression

“…Growing evidence shows that miRNAs are extensively involved in the pathogenesis of heart diseases (15), including cardiac hypertrophy (30), cardiac fibrosis (36), arrhythmia (43), heart failure (33), and MI (16,27). The miR-30 family, including miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e, has been shown to alter cell proliferation, differentiation (37), migration, and invasion (6) in various carcinomas.…”