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
-
- Collagen
- MicroRNAs/antagonists & inhibitors
- MicroRNAs/genetics
- MicroRNAs/physiology*
- Gene Expression Profiling
- Drug Combinations
- Arterioles/pathology
- p21-Activated Kinases/biosynthesis
- p21-Activated Kinases/genetics
- Cell Hypoxia
- Ventricular Remodeling
- Heart Failure/etiology
- Zebrafish Proteins/biosynthesis
- Zebrafish Proteins/genetics
- Cells, Cultured/drug effects
- Cells, Cultured/metabolism
- Zebrafish/embryology
- Capillaries/pathology
- Endothelial Cells/metabolism*
- Endothelial Cells/pathology
- GATA2 Transcription Factor/biosynthesis
- GATA2 Transcription Factor/genetics
- Laminin
- Male
- Oligoribonucleotides/pharmacology
- Animals
- Neovascularization, Physiologic/drug effects
- Neovascularization, Physiologic/genetics
- Mice
- Myocardial Infarction/complications
- Myocardial Infarction/genetics
- Myocardial Infarction/physiopathology*
- Mice, Inbred C57BL
- RNA, Small Interfering/pharmacology
- RNA, Small Interfering/therapeutic use
- RNA Interference
- Heme Oxygenase-1/biosynthesis
- Heme Oxygenase-1/genetics
- Proteoglycans
- Drug Evaluation, Preclinical
- Spheroids, Cellular
- Apoptosis/drug effects
- 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.