MicroRNA-24 Regulates Vascularity After Myocardial Infarction

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.
Circulation   124(6): 720-30 (Journal)
Registered Authors
Brand, Thomas, Schulte-Merker, Stefan
myocaridal infarction, microRNAs, angiogenesis, antagomir, gene expression, heart failure
MeSH Terms
  • Animals
  • Apoptosis/drug effects
  • Arterioles/pathology
  • Capillaries/pathology
  • Cell Hypoxia
  • Cells, Cultured/drug effects
  • Cells, Cultured/metabolism
  • Collagen
  • Drug Combinations
  • Drug Evaluation, Preclinical
  • Endothelial Cells/metabolism*
  • Endothelial Cells/pathology
  • GATA2 Transcription Factor/biosynthesis
  • GATA2 Transcription Factor/genetics
  • Gene Expression Profiling
  • Heart Failure/etiology
  • Heme Oxygenase-1/biosynthesis
  • Heme Oxygenase-1/genetics
  • Laminin
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs/antagonists & inhibitors
  • MicroRNAs/genetics
  • MicroRNAs/physiology*
  • Myocardial Infarction/complications
  • Myocardial Infarction/genetics
  • Myocardial Infarction/physiopathology*
  • Neovascularization, Physiologic/drug effects
  • Neovascularization, Physiologic/genetics
  • Oligoribonucleotides/pharmacology
  • Proteoglycans
  • RNA Interference
  • RNA, Small Interfering/pharmacology
  • RNA, Small Interfering/therapeutic use
  • Spheroids, Cellular
  • Ventricular Remodeling
  • Zebrafish/embryology
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/genetics
  • p21-Activated Kinases/biosynthesis
  • p21-Activated Kinases/genetics
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.

Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes