title: 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.
  
  
  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.
authors.affiliation: Hannover Medical School, Institute for Molecular and Translational Therapeutic Strategies, Hannover, Germany. Thum.Thomas@mh-hannover.de
authors.forename: Jan
authors.initials: J
authors.lastname: Fiedler
authors.forename: Virginija
authors.initials: V
authors.lastname: Jazbutyte
authors.forename: Bettina C
authors.initials: BC
authors.lastname: Kirchmaier
authors.forename: Shashi K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Johan
authors.initials: J
authors.lastname: Lorenzen
authors.forename: Dorothee
authors.initials: D
authors.lastname: Hartmann
authors.forename: Paolo
authors.initials: P
authors.lastname: Galuppo
authors.forename: Susanne
authors.initials: S
authors.lastname: Kneitz
authors.forename: John T G
authors.initials: JT
authors.lastname: Pena
authors.forename: Cherin
authors.initials: C
authors.lastname: Sohn-Lee
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.forename: Juergen
authors.initials: J
authors.lastname: Soutschek
authors.forename: Thomas
authors.initials: T
authors.lastname: Brand
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Joerg
authors.initials: J
authors.lastname: Heineke
authors.forename: Ulrich
authors.initials: U
authors.lastname: Martin
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Stefan
authors.initials: S
authors.lastname: Engelhardt
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001160:Arterioles / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D015687:Cell Hypoxia; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D003094:Collagen; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D050989:GATA2 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000209:etiology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D007797:Laminin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D009843:Oligoribonucleotides / Q000494:pharmacology; D011509:Proteoglycans; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D018874:Spheroids, Cellular; D020257:Ventricular Remodeling; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics; D054462:p21-Activated Kinases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D004338:Drug Combinations; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C516059:Gata2a protein, zebrafish; D007797:Laminin; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; C529080:Mirn24 microRNA, mouse; D009843:Oligoribonucleotides; D011509:Proteoglycans; D034741:RNA, Small Interfering; D029961:Zebrafish Proteins; C059485:matrigel; D003094:Collagen; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C116367:PAK4 protein, human; D054462:p21-Activated Kinases