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

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 home 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-I 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 (C) 2010 Elsevier Inc All rights reserved