COX-1^+/-COX-2^-/- genotype in mice is associated with shortened time to carotid artery occlusion through increased PAI-1

Background:We found a high incidence of thrombotic deaths in COX-1^+/-COX-2^-/- mice and sought to define the mechanism of these events. The cyclooxygenase products thromboxane A₂ and prostacyclin are important in the regulation of coagulation but their role in fibrinolysis is largely unexplored. PAI-1 blocks fibrinolysis by inhibiting plasminogen activator. Aim:Our objective was to explain the mechanism of increased thrombosis associated with the COX-1^+/-COX-2^-/- genotype. Methods:Carotid artery occlusion times were measured after photochemical injury. PAI-1 levels were measured in the plasma by ELISA. PAI-1 levels in the aorta were measured by RT-PCR and Western blotting. Urinary metabolites of Thromboxane A₂ and prostacyclin were measured by ELISA. Results:The COX-1^+/-COX-2^-/- genotype is associated with a decreased time to occlusion in the carotid artery thrombosis model (30±5minutes vs 60± minutes in wild type, p<001). The COX-1^-/-COX-2^+/+, COX-1^+/-COX-2^+/- and COX-1^+/- COX-2^+/+ all had occlusion times similar to wild type. COX-1^+/+ COX-2^-/- had a prolonged occlusion time. COX-1^+/- COX-2^-/- had increased PAI-1 levels in the plasma and aorta and with a prolonged euglobulin lysis time (37.4±10.2hours vs 15.6±9.8hours in wild type, p<004). The decreased time to occlusion in the COX-1^+/-COX2^-/- mice was normalized by an inhibitory antibody to PAI-1 whereas the antibody had no effect on the time to occlusion in wild type mice. Conclusion:The COX-1^+/-COX-2^-/- genotype is associated with a shortened time to occlusion in the carotid thrombosis model and the shortened time to occlusion is mediated through increased PAI-1 levels resulting in decreased fibrinolysis.