title: The β3-integrin binding protein β3-endonexin is a novel negative regulator of hypoxia-inducible factor-1.
abstract: OBJECTIVE
  Integrins are multifunctional heterodimeric adhesion receptors that mediate the attachment between a cell and the extracellular matrix or other surrounding cells. In endothelial cells, integrins can modulate cell migration and motility. In particular, β3-integrin is expressed in angiogenic vessels. Signal transduction by β3-integrins requires the recruitment of intracellular signaling molecules. β3-endonexin is a highly spliced molecule that has been identified as a β3-integrin binding protein. β3-endonexin isoforms are expressed in endothelial cells and have been suggested to act as shuttle proteins between the membrane and the nucleus. However, their functional role in angiogenesis is unclear. In this study, we investigated whether β3-endonexin isoforms are involved in endothelial angiogenic processes under hypoxia.
  
  
  RESULTS
  The overexpression of β3-endonexin isoforms decreased endothelial proliferation and tube formation under hypoxia, while the depletion of β3-endonexin by RNAi promoted angiogenic responses in vitro and in vivo. In hypoxia, β3-endonexin accumulated in the nucleus, and prevention of this response by depletion of β3-endonexin increased hypoxic activation and induction of the hypoxia-inducible factor (HIF)-1 and its target genes VEGF and PAI-1. β3-endonexin diminished nuclear factor kappa B (NFκB) activation and decreased NFκB binding to the HIF-1α promoter under hypoxia, subsequently diminishing NFκB-dependent transcription of HIF-1α under hypoxia.
  
  
  METHODS
  Our results indicate for the first time that the overexpression of β3-endonexin can decrease hypoxic induction and activation of HIF-1α and can prevent hypoxic endothelial proliferation and angiogenic responses.
  
  
  CONCLUSIONS
  β3-endonexin can act as a novel anti-angiogenic factor specifically in the response to hypoxia due to its negative impact on the activation of HIF-1.
authors.affiliation: 1 Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Technical University Munich , Munich, Germany.
authors.forename: Damir
authors.initials: D
authors.lastname: Kračun
authors.forename: Florian
authors.initials: F
authors.lastname: Riess
authors.forename: Ivan
authors.initials: I
authors.lastname: Kanchev
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.forename: Agnes
authors.initials: A
authors.lastname: Görlach
mesh_terms: D020533:Angiogenesis Inhibitors / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C405619:HIGD1A protein, human; C403295:ITGB3BP protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger