title: Altered oxidative stress responses and increased type I collagen expression in bicuspid aortic valve patients.
abstract: BACKGROUND
  The mechanisms governing extracellular matrix degradation and smooth muscle cell (SMC) loss in the ascending aorta of bicuspid aortic valve (BAV) patients are unknown. We recently reported that expression and induction of metallothionein, a reactive oxygen species scavenger, is reduced in BAV ascending aortic aneurysms relative to nonaneurysmal patients.
  
  
  METHODS
  Tissue and primary SMCs from patients with and without thoracic aortic aneurysms and metallothionein-null and wild-type mice were analyzed for cell viability, vascular endothelial growth factor (VEGF), and type I collagen gene expression during exposure to reactive oxygen species.
  
  
  RESULTS
  The BAV SMCs and metallothionein -/- mice failed to induce VEGF under conditions of oxidative stress in vitro. Exogenous VEGF restored resistance to oxidative stress in BAV SMCs to normal. Type I collagen gene induction was increased in BAV aorta.
  
  
  CONCLUSIONS
  Lack of VEGF induction during exposure to reactive oxygen species suggest that the oxidative stress response is faulty upstream of metallothionein and VEGF in BAV SMCs. Improvement of cell viability with VEGF treatment suggests that the deficient pathway can be rescued by VEGF. Increased type I collagen in BAV suggests that lack of metallothionein/VEGF activation in response to reactive oxygen species may play a role in extracellular matrix homeostasis of the ascending aorta. These data continue to support our hypothesis that BAV SMCs lack sufficient resistance to reactive oxygen species to maintain extracellular matrix homeostasis, which imparts a predisposition to thoracic aortic aneurysms.
authors.affiliation: Department of Cardiothoracic Surgery, Center for Thoracic Aortic Disease, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Phillippi
authors.forename: Michael A
authors.initials: MA
authors.lastname: Eskay
authors.forename: Adam A
authors.initials: AA
authors.lastname: Kubala
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Pitt
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gleason
mesh_terms: D000328:Adult; D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities / Q000378:metabolism*; D024042:Collagen Type I / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006349:Heart Valve Diseases / Q000151:congenital / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011379:Prognosis; D012313:RNA / Q000096:biosynthesis / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D012313:RNA