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Fiedler, Jan; Jazbutyte, Virginija; Kirchmaier, Bettina C.; Gupta, Shashi K.; Lorenzen, Johan; Hartmann, Dorothee; Galuppo, Paolo; Kneitz, Susanne; Pena, John T.G.; Sohn-Lee, Cherin; Loyer, Xavier; Soutschek, Juergen; Brand, Thomas; Tuschl, Thomas; Heineke, Joerg; Martin, Ulrich; Schulte-Merker, Stefan; Ertl, Georg; Engelhardt, Stefan; Bauersachs, Johann; Thum, Thomas

MicroRNA-24 Regulates Vascularity After Myocardial Infarction

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  • Medientyp: E-Artikel
  • Titel: MicroRNA-24 Regulates Vascularity After Myocardial Infarction
  • Beteiligte: Fiedler, Jan; Jazbutyte, Virginija; Kirchmaier, Bettina C.; Gupta, Shashi K.; Lorenzen, Johan; Hartmann, Dorothee; Galuppo, Paolo; Kneitz, Susanne; Pena, John T.G.; Sohn-Lee, Cherin; Loyer, Xavier; Soutschek, Juergen; Brand, Thomas; Tuschl, Thomas; Heineke, Joerg; Martin, Ulrich; Schulte-Merker, Stefan; Ertl, Georg; Engelhardt, Stefan; Bauersachs, Johann; Thum, Thomas
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2011
  • Erschienen in: Circulation
  • Sprache: Englisch
  • DOI: 10.1161/circulationaha.111.039008
  • ISSN: 0009-7322; 1524-4539
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec> <jats:title>Background—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang