title: Celecoxib activates PI-3K/Akt and mitochondrial redox signaling to enhance heme oxygenase-1-mediated anti-inflammatory activity in vascular endothelium.
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.
authors.affiliation: Cardiovascular Sciences, Bywaters Center for Vascular Inflammation, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London W12 ONN, UK.
authors.forename: Shahir S
authors.initials: SS
authors.lastname: Hamdulay
authors.forename: Bufei
authors.initials: B
authors.lastname: Wang
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Birdsey
authors.forename: Faisal
authors.initials: F
authors.lastname: Ali
authors.forename: Odile
authors.initials: O
authors.lastname: Dumont
authors.forename: Paul C
authors.initials: PC
authors.lastname: Evans
authors.forename: Dorian O
authors.initials: DO
authors.lastname: Haskard
authors.forename: Caroline P
authors.initials: CP
authors.lastname: Wheeler-Jones
authors.forename: Justin C
authors.initials: JC
authors.lastname: Mason
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000068579:Celecoxib; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000494:pharmacology; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011524:Protoporphyrins / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D002867:Chromones; C549075:LY 290042; D007783:Lactones; D009025:Morpholines; D051267:NF-E2-Related Factor 2; D011524:Protoporphyrins; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C116926:rofecoxib; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib; D000111:Acetylcysteine