Abstract 136: C-Reactive Protein Accelerates Thrombosis by Modulating Arachidonic Acid - Cyclooxygenase Pathways
Background: Recent data supports a role for C-reactive protein (CRP) as a mediator of increased thrombogenicity and thus an increased risk of vascular disease. The present study examined whether and how CRP affects the arachidonic-acid cyclooxygenase (COX)-mediated pathways in transgenic mice that express human CRP (CRPtg)
Methods and Results: CRPtg and littermate C57/BL wildtypes were subjected to femoral artery wire injury. The expression of key genes in the prostanoid pathway was measured by real time PCR and Western Blot in the injured arteries and in the distant lung tissue, at baseline, 6hr, and 24hr after injury (n=5–7/group). The expression of COX-2, prostacyclin synthase and prostacyclin receptor after vascular injury was significantly reduced in CRPtg mice while thromboxane synthase and thromboxane receptor expression were significantly augmented. Immunohistochemcial staining confirmed the reduced expression of COX-2 and the elevated expression of thromboxane receptor in the injured arteries of CRPtg mice. Urinary prostacyclin metabolites were significantly reduced in CRPtg as compared with wildtypes. Aspirin therapy (30 mg/kg/day starting two weeks prior to injury) reversed the prothrombotic effect of CRP as measured by reduced carotid thrombosis following photochemical injury and prostanoid pathway gene expression.
Conclusions: In mice transgenic for human CRP, arachidonic-acid cyclooxygenase pathways are modulated towards suppressed prostacyclin expression and increased thromboxane activity. These effects may promote thrombosis in response to injury and may provide rationalization for the increased incidence of vascular events that is associated with high CRP levels.