MicroRNA-24 Regulates Vascularity After Myocardial Infarction
- Authors
- Fiedler, J., Jazbutyte, V., Kirchmaier, B.C., Gupta, S.K., Lorenzen, J., Hartmann, D., Galuppo, P., Kneitz, S., Pena, J.T., Sohn-Lee, C., Loyer, X., Soutschek, J., Brand, T., Tuschl, T., Heineke, J., Martin, U., Schulte-Merker, S., Ertl, G., Engelhardt, S., Bauersachs, J., and Thum, T.
- ID
- ZDB-PUB-110803-11
- Date
- 2011
- Source
- Circulation 124(6): 720-30 (Journal)
- Registered Authors
- Brand, Thomas, Schulte-Merker, Stefan
- Keywords
- myocaridal infarction, microRNAs, angiogenesis, antagomir, gene expression, heart failure
- MeSH Terms
-
- Animals
- Apoptosis/drug effects
- Arterioles/pathology
- Capillaries/pathology
- Cell Hypoxia
- PubMed
- 21788589 Full text @ Circulation
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.