Role of thromboxane receptor in c-reactive protein-induced thrombosis

OBJECTIVE-: Thromboxane A2 and prostacyclin are thromboregulatory prostaglandins. The inflammatory C-reactive protein (CRP) promotes thrombosis after vascular injury, presumably via potentiation of thromboxane activity. Using a genetic approach, we investigated the role of thromboxane receptor (TP^-/-) pathway in CRP-induced thrombosis. METHODS AND RESULTS-: Four genetically engineered mice strains were used: C57BL/6 wild-type, human CRP transgenic (CRPtg), thromboxane receptor-deficient (Tp^-/-), and CRPtgTp^-/- mice. CRP and TP^-/- expression were correlated, and suppression of CRP expression using small interfering RNA/CRP led to reduction in TP^-/- expression. Platelet-endothelial adherence was increased in CRPtg and suppressed in CRPtgTP^-/- and CRPtg cells that were suppressed with TP^-/- small interfering RNA. TP^-/- deficiency in both platelets and endothelial cells was synergistic in affecting platelet-endothelial interactions. Time until arterial occlusion, measured after photochemical injury, was significantly shorter in CRPtg and prolonged in CRPtgTp^-/- compared with controls (n=10-15, 35±3.4, 136±13.8, and 67±8.9 minutes, respectively; P<0.05). CONCLUSION-: TP^-/- pathway is of major importance in CRP-induced thrombosis. The expression of TP^-/- is increased in CRPtg endothelial cells, and its blockade significantly suppresses the prothrombotic effect of CRP.