COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation

Mallika Ghosh, Haibin Wang, Youxi Ai, Elisa Romeo, James P. Luyendyk, Jeffrey M. Peters, Nigel Mackman, Sudhansu K. Dey, Timothy Hla

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


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 (PGI2) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator-activated receptor (PPAR) δ, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPARδ activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPARδ 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, PPARδ agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects. JEM

Original languageEnglish (US)
Pages (from-to)2053-2061
Number of pages9
JournalJournal of Experimental Medicine
Issue number9
StatePublished - Sep 3 2007

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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