title: MicroRNA-mediated epigenetic silencing of sirtuin1 contributes to impaired angiogenic responses.
abstract: BACKGROUND
  Transforming growth factor (TGF)-β was linked to abnormal vessel function and can mediate impairment of endothelial angiogenic responses. Its effect on microRNAs and downstream targets in this context is not known.
  
  
  OBJECTIVE
  To study the role of microRNAs in TGF-β-mediated angiogenic activity.
  
  
  RESULTS
  MicroRNA profiling after TGF-β treatment of endothelial cells identified miR-30a-3p, along with other members of the miR-30 family, to be strongly silenced. Supplementation of miR-30a-3p restored function in TGF-β-treated endothelial cells. We identified the epigenetic factor methyl-CpG-binding protein 2 (MeCP2) to be a direct and functional target of miR-30a-3p. Viral overexpression of MeCP2 mimicked the effects of TGF-β, suggesting that derepression of MeCP2 after TGF-β treatment may be responsible for impaired angiogenic responses. Silencing of MeCP2 rescued detrimental TGF-β effects on endothelial cells. Microarray transcriptome analysis of MeCP2-overexpressing endothelial cells identified several deregulated genes important for endothelial cell function including sirtuin1 (Sirt1). In vivo experiments using endothelial cell-specific MeCP2 null or Sirt1 transgenic mice confirmed the involvement of MeCP2/Sirt1 in the regulation of angiogenic functions of endothelial cells. Additional experiments identified that MeCP2 inhibited endothelial angiogenic characteristics partly by epigenetic silencing of Sirt1.
  
  
  CONCLUSIONS
  TGF-β impairs endothelial angiogenic responses partly by downregulating miR-30a-3p and subsequent derepression of MeCP2-mediated epigenetic silencing of Sirt1.
authors: From the Institute of Molecular and Translational Therapeutic Strategies.
authors: Ingo
authors: I
authors: Volkmann
authors: Regalla
authors: R
authors: Kumarswamy
authors: Nils
authors: N
authors: Pfaff
authors: Jan
authors: J
authors: Fiedler
authors: Seema
authors: S
authors: Dangwal
authors: Angelika
authors: A
authors: Holzmann
authors: Sandor
authors: S
authors: Batkai
authors: Robert
authors: R
authors: Geffers
authors: Achim
authors: A
authors: Lother
authors: Lutz
authors: L
authors: Hein
authors: Thomas
authors: T
authors: Thum
mesh_terms: D000818:Animals; D002465:Cell Movement; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D020868:Gene Silencing; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014162:Transfection; D053781:Transforming Growth Factor beta2 / Q000378:metabolism
chemical_list: C497392:MECP2 protein, human; C546086:MIRN30b microRNA, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; C534715:Mirn30d microRNA, mouse; D053781:Transforming Growth Factor beta2; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: angiogenic responses; endothelial cells; epigenomics; methyl-CpG-binding protein 2; microRNAs; sirt1 protein, mouse; transforming growth factor beta