title: Local inhibition of hypoxia-inducible factor reduces neointima formation after arterial injury in ApoE-/- mice.
abstract: OBJECTIVE
  Hypoxia plays a pivotal role in development and progression of restenosis after vascular injury. Under hypoxic conditions the hypoxia-inducible factors (HIFs) are the most important transcription factors for the adaption to reduced oxygen supply. Therefore the aim of the study was to investigate the effect of a local HIF-inhibition and overexpression on atherosclerotic plaque development in a murine vascular injury model.
  
  
  RESULTS
  After wire-induced vascular injury in ApoE-/- mice a transient, local inhibition of HIF as well as an overexpression approach of the different HIF-subunits (HIF-1α, HIF-2α) by adenoviral infection was performed. The local inhibition of the HIF-pathway using a dominant-negative mutant dramatically reduced the extent of neointima formation. The diminished plaque size was associated with decreased expression of the well-known HIF-target genes vascular endothelial growth factor-A (VEGF-A) and its receptors Flt-1 and Flk-1. In contrast, the local overexpression of HIF-1α and HIF-2α further increased the plaque size after wire-induced vascular injury.
  
  
  CONCLUSIONS
  Local HIF-inhibition decreases and HIF-α overexpression increases the injury induced neointima formation. These findings provide new insight into the pathogenesis of atherosclerosis and may lead to new therapeutic options for the treatment of in stent restenosis.
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Christoph
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Karim
authors.initials: K
authors.lastname: Ibrahim
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hesse
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Augstein
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schmeisser
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Simonis
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Wunderlich
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Silvio
authors.initials: S
authors.lastname: Quick
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany.
authors.forename: Ruth H
authors.initials: RH
authors.lastname: Strasser
authors.affiliation: University of Dresden, Heart Center, University Hospital, Germany. Electronic address: david.poitz@tu-dresden.de.
authors.forename: David M
authors.initials: DM
authors.lastname: Poitz
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D023903:Coronary Restenosis; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000293:injuries; D005263:Femoral Artery / Q000293:injuries* / Q000473:pathology; D005822:Genetic Vectors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058426:Neointima / Q000517:prevention & control*; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000517:prevention & control*; D015398:Signal Transduction; D014161:Transduction, Genetic; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D001057:Apolipoproteins E; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse
keywords: Atherosclerosis; Hypoxia; Hypoxia-inducible factor; Restenosis