Celecoxib activates PI-3K/Akt and mitochondrial redox signaling to enhance heme oxygenase-1-mediated anti-inflammatory activity in vascular endothelium

Free Radic Biol Med. 2010 Apr 15;48(8):1013-23. doi: 10.1016/j.freeradbiomed.2010.01.017. Epub 2010 Jan 18.

Abstract

Although nonsteroidal anti-inflammatory drugs (NSAIDs) provide important control of pain and inflammation, they have been overshadowed by concerns regarding atherothrombotic complications. However, celecoxib seems to have a relatively good cardiovascular profile and may improve endothelial function in coronary heart disease. This led us to the hypothesis that celecoxib induces the vasculoprotective enzyme heme oxygenase-1 (HO-1). In human umbilical vein and aortic endothelial cells, 24-48 h treatment with celecoxib induced HO-1 mRNA and protein expression and increased HO-1 enzyme activity. This effect was not seen with rofecoxib or indomethacin. Supplementation of culture medium with iloprost or prostaglandin E(2) failed to reverse celecoxib-mediated HO-1 induction, indicating a cyclooxygenase-independent mechanism. Rather, this action of celecoxib involved generation of mitochondria-derived reactive oxygen species, Akt phosphorylation, and nuclear translocation of the transcription factor Nrf2, with N-acetylcysteine, PI-3K antagonist LY290042, and dominant-negative Akt abrogating the effects. Furthermore, celecoxib-induced HO-1 was inhibited by dominant-negative Nrf2. The functional significance of HO-1 induction was revealed by celecoxib-mediated inhibition of VCAM-1 expression, a response reversed by the HO-1 antagonist zinc protoporphyrin. HO-1 induction provides a molecular mechanism for clinical observations indicating relative freedom from atherothrombotic complications in patients taking celecoxib compared to other NSAIDs with comparable anti-inflammatory activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Celecoxib
  • Chromones / pharmacology
  • Endothelial Cells / drug effects
  • Enzyme Induction
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Lactones / pharmacology
  • Morpholines / pharmacology
  • NF-E2-Related Factor 2 / pharmacology
  • Oxidation-Reduction
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Protoporphyrins / pharmacology
  • Pyrazoles / pharmacology*
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology*
  • Sulfones / pharmacology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Vascular Cell Adhesion Molecule-1 / biosynthesis

Substances

  • Chromones
  • LY 290042
  • Lactones
  • Morpholines
  • NF-E2-Related Factor 2
  • Protoporphyrins
  • Pyrazoles
  • Sulfonamides
  • Sulfones
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • rofecoxib
  • zinc protoporphyrin
  • Heme Oxygenase-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Celecoxib
  • Acetylcysteine