title: Upregulation of glutathione peroxidase offsets stretch-induced proatherogenic gene expression in human endothelial cells.
abstract: OBJECTIVE
  Localization of atherosclerotic plaques typically correlates with areas of biomechanical strain where shear stress is decreased while stretch, thought to promote atherogenesis through enhanced oxidative stress, is increased.
  
  
  RESULTS
  In human cultured endothelial cells, nitric oxide synthase expression was exclusively shear stress-dependent whereas expression of glutathione peroxidase-1 (GPx-1), but not that of Cu(2+)/Zn(2+)-superoxide dismutase or Mn(2+)-superoxide dismutase, was upregulated solely in response to cyclic stretch. GPx-1 expression was also enhanced in isolated mouse arteries perfused at high pressure. Combined pharmacological and decoy oligodeoxynucleotide blockade revealed that activation of p38 MAP kinase followed by nuclear translocation of CCAAT/enhancer binding protein plays a pivotal role in stretch-induced GPx-1 expression in human endothelial cells. Antisense oligodeoxynucleotide knockdown of GPx-1 reinforced both their capacity to generate hydrogen peroxide and the transient stretch-induced expression of CD40, monocyte chemoatractant protein-1, and vascular cell adhesion molecule-1. Consequently, THP-1 monocyte adhesion to the GPx-1-depleted cells was augmented.
  
  
  CONCLUSIONS
  Stretch-induced proatherosclerotic gene expression in human endothelial cells seems to be hydrogen peroxide-mediated. The concomitant rise in GPx-1 expression, but not that of other antioxidant enzymes, may comprise an adaptive mechanism through which the cells maintain their antiatherosclerotic properties in spite of a decreased bioavailability of nitric oxide.
authors.affiliation: Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Wagner
authors.forename: Ocko
authors.initials: O
authors.lastname: Kautz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Fricke
authors.forename: Murielle
authors.initials: M
authors.lastname: Zerr-Fouineau
authors.forename: Elena
authors.initials: E
authors.lastname: Demicheva
authors.forename: Björn
authors.initials: B
authors.lastname: Güldenzoph
authors.forename: Justo Lorenzo
authors.initials: JL
authors.lastname: Bermejo
authors.forename: Thomas
authors.initials: T
authors.lastname: Korff
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000201:enzymology*; D004789:Enzyme Activation / Q000235:genetics; D005786:Gene Expression Regulation; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013314:Stress, Mechanical; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D019001:Nitric Oxide Synthase