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COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARdelta activation
Mallika Ghosh1, Haibin Wang, Youxi Ai
1Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.
The Journal of Experimental Medicine
|August 29, 2007
Summary
Cyclooxygenase-2 inhibitors (coxibs) may increase cardiovascular risks by suppressing tissue factor expression. PPARdelta agonists can potentially counteract these prothrombotic effects, offering therapeutic possibilities.
Area of Science:
- Biomedical Science
- Pharmacology
- Cardiovascular Research
Background:
- Cyclooxygenase-2 (COX-2) inhibitors (coxibs) effectively manage inflammation, pain, and tumorigenesis.
- However, coxibs are associated with increased adverse cardiovascular events, with unclear mechanisms.
- Tissue factor (TF) is a primary initiator of blood coagulation.
Purpose of the Study:
- To elucidate the mechanistic basis of coxib-induced cardiovascular side effects.
- To investigate the role of peroxisomal proliferator-activated receptor (PPAR) delta in regulating tissue factor (TF) expression.
- To explore the therapeutic potential of PPARdelta agonists in mitigating coxib-related cardiovascular risks.
Main Methods:
- Investigated the interaction between endothelial cell COX-2, prostacyclin synthase (PGIS), and endocannabinoid metabolism.
- Assessed the activation of PPARdelta by COX-2 activity.
- Measured TF expression and activity in vascular endothelium and circulation in vivo.
- Evaluated the effects of coxibs and PPARdelta agonists on TF expression and activity.
Main Results:
- Endothelial cell COX-2 metabolism activates PPARdelta, which suppresses TF expression.
- Coxibs inhibit PPARdelta activity, leading to increased TF expression and circulating TF activity.
- PPARdelta agonists counteract coxib-induced TF expression and reduce circulating TF activity.
- COX-2-dependent TF expression attenuation is abrogated by coxibs.
Conclusions:
- Coxibs may induce prothrombotic side effects by suppressing the PPARdelta-mediated downregulation of TF.
- PPARdelta agonists show therapeutic promise for preventing or treating coxib-induced cardiovascular complications.
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