Cyclooxygenase-2-Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a SIRT1-Dependent-Manner
Background—Selective inhibitors of cyclooxygenase-2 (COX-2) increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood.
Methods and Results—We found that ferric chloride-induced arterial thrombus formation was significantly greater in COX-2 knockout (KO) compared to wild type (WT) mice. Cross-transfusion experiments excluded the likelihood that COX-2KO platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2KO mice. Importantly, we observed that COX-2 deletion decreased prostacyclin (PGI2) synthase and production, proliferator-activated receptor (PPAR)δ and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of WT mice with a PGI2 receptor (IP) antagonist or a PPARδ antagonist, which predisposes to arterial thombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous PGI2 or PPARδ agonist completely reversed the thrombotic phenotype in COX-2KO mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity, and promoted generation of occlusive thrombi in WT mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2KO mice.
Conclusions—Modulation of SIRT1 and hence TF by PGI2/PPARδ pathways not only represents a new mechanism in controlling arterial thrombus formation, but also might be a useful target for therapeutic intervention in the arterothrombotic complications associated with COX-2 inhibitors.
- Received February 16, 2012.
- Accepted July 20, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited