COX-2 deletion in mice significantly increased arterial thrombus formation by decreasing prostacyclin and SIRT1 expression, leading to upregulated tissue factor activity.
Does COX-2 deletion increase arterial thrombus formation via SIRT1 and tissue factor pathways in mice?
COX-2 deletion promotes arterial thrombosis by downregulating SIRT1 and upregulating tissue factor via prostacyclin/PPAR-δ pathways, providing a mechanistic explanation for the thrombotic risk of COX-2 inhibitors.
BACKGROUND: Selective inhibitors of cyclooxygenase (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 compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor- and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-δ antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor-δ agonist completely reversed the thrombotic phenotype in COX-2 knockout 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 wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice. CONCLUSIONS: Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-δ pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors.
Barbieri et al. (2012) studied Arterial thrombus formation. COX-2 deletion vs. Wild-type mice was evaluated on Ferric chloride-induced arterial thrombus formation. COX-2 deletion in mice significantly increased arterial thrombus formation by decreasing prostacyclin and SIRT1 expression, leading to upregulated tissue factor activity.