期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 204, 期 9, 页码 2053-2061出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20070828
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资金
- NCI NIH HHS [CA 77839, P01 CA077839] Funding Source: Medline
- NHLBI NIH HHS [R01 HL048872, HL 48872, R01 HL049094, HL 49094] Funding Source: Medline
- NIDA NIH HHS [R01 DA006668, DA 006668, R37 DA006668] Funding Source: Medline
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 PPAR delta activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPAR delta 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, PPAR delta agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects.
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