Hypoxia induces nitric oxide synthase in rheumatoid synoviocytes: consequences on NADPH oxidase regulation

Free Radic Res. 2012 May;46(5):628-36. doi: 10.3109/10715762.2012.662276. Epub 2012 Mar 12.


We investigated the effects of hypoxia on inducible NO synthase (iNOS) activity and expression in rheumatoid arthritis (RA) synoviocytes. We further studied the relationship between nitrosative stress and NADPH oxidase (NOX) in such conditions. Human cultured synoviocytes were treated for 24 hours with IL-1β, TNF-α or neither, and submitted to hypoxia or normoxia for the last 6 hours. Nitrite production and iNOS expression were increased under hypoxia conditions in RA cells in comparison to normoxia. Hypoxia did not potentate the basal and cytokine-induced superoxide productions, while NOXs' subunit expression and p47-phox phosphorylation were increased. Nitrosylation of NOXs and p47-phox was not raised under hypoxia conditions. Finally, peroxynitrite production was significantly increased under hypoxia conditions, in comparison to normoxia. Our results provide evidence for upregulation of iNOS and NOX activities in RA synoviocytes under hypoxia conditions, associated to an increased peroxynitrite production. Synovial cell metabolism under hypoxia conditions might be different from that in normoxia.

MeSH terms

  • Adult
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Cell Hypoxia*
  • Cells, Cultured
  • Female
  • Humans
  • Interleukin-1beta / pharmacology
  • Male
  • Middle Aged
  • NADPH Oxidases / metabolism*
  • Nitric Oxide Synthase Type II / biosynthesis
  • Nitric Oxide Synthase Type II / metabolism*
  • Nitrites / metabolism
  • Oxidative Stress
  • Peroxynitrous Acid / metabolism
  • Phosphorylation
  • Synovial Fluid / metabolism
  • Synovial Membrane / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Interleukin-1beta
  • Nitrites
  • Tumor Necrosis Factor-alpha
  • Peroxynitrous Acid
  • Nitric Oxide Synthase Type II
  • NADPH Oxidases
  • neutrophil cytosolic factor 1