COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation.
Although cyclooxygenase (COX)-2 inhibitors (coxibs) are effective in controlling inflammation, pain, and tumorigenesis, their use is limited by the recent revelation of increased adverse cardiovascular events. The mechanistic basis of this side effect is not well understood. We show that the metabolism of endocannabinoids by the endothelial cell COX-2 coupled to the prostacyclin (PGI(2)) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator-activated receptor (PPAR) delta, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPARdelta activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPARdelta agonists suppress coxib-induced TF expression and decrease circulating TF activity. We provide evidence that COX-2-dependent attenuation of TF expression is abrogated by coxibs, which may explain the prothrombotic side-effects for this class of drugs. Furthermore, PPARdelta agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects.
Ghosh
Mallika
M
Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
Wang
Haibin
H
Ai
Youxi
Y
Romeo
Elisa
E
Luyendyk
James P
JP
Peters
Jeffrey M
JM
Mackman
Nigel
N
Dey
Sudhansu K
SK
Hla
Timothy
T
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D063388:Endocannabinoids; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013925:Thromboplastin / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D063385:Cannabinoid Receptor Modulators; D052246:Cyclooxygenase 2 Inhibitors; D063388:Endocannabinoids; D047494:PPAR delta; D011720:Pyrazoles; D013449:Sulfonamides; D013925:Thromboplastin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib