title: Transforming growth factor-β-induced endothelial-to-mesenchymal transition is partly mediated by microRNA-21.
abstract: OBJECTIVE
  MicroRNAs are a class of small ribonucleotides regulating gene/protein targets by transcript degradation or translational inhibition. Transforming growth factor-β (TGF-β) is involved in cardiac fibrosis partly by stimulation of endothelial-to-mesenchymal transition (EndMT). Here, we investigated whether microRNA (miR)-21, a microRNA enriched in fibroblasts and involved in general fibrosis, has a role in cardiac EndMT.
  
  
  RESULTS
  TGF-β treatment of endothelial cells significantly increased miR-21 expression and induced EndMT characterized by suppression of endothelial and increase of fibroblast markers. Overexpression of miR-21 alone also stimulated EndMT. Importantly, miR-21 blockade by transfection of specific microRNA inhibitors partly prevented TGF-β-induced EndMT. Mechanistically, miR-21 silenced phosphatase and tensin homolog in endothelial cells, resulting in activation of the Akt-pathway. Akt inhibition partly restored TGF-β-mediated loss of endothelial markers during EndMT. In vivo, pressure overload of the left ventricle led to increased expression of miR-21 in sorted cardiac endothelial cells, which displayed molecular and phenotypic signs of EndMT. This was attenuated by treatment of mice subjected to left ventricular pressure overload with an antagomir against miR-21.
  
  
  CONCLUSIONS
  TGF-β-mediated EndMT is regulated at least in part by miR-21 via the phosphatase and tensin homolog/Akt pathway. In vivo, antifibrotic effects of miR-21 antagonism are partly mediated by blocking EndMT under stress conditions.
authors.affiliation: Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Carl-Neuberg-Str 1, 30625 Hannover, Germany.
authors.forename: Regalla
authors.initials: R
authors.lastname: Kumarswamy
authors.forename: Ingo
authors.initials: I
authors.lastname: Volkmann
authors.forename: Virginija
authors.initials: V
authors.lastname: Jazbutyte
authors.forename: Seema
authors.initials: S
authors.lastname: Dangwal
authors.forename: Da-Hee
authors.initials: DH
authors.lastname: Park
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D054338:Cell Transdifferentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D035683:MicroRNAs / Q000502:physiology*; D008840:Microfilament Proteins / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000070876:Tensins; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D008840:Microfilament Proteins; D000070876:Tensins; D016212:Transforming Growth Factor beta; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human