In the present study, we assessed if the platelet inhibitory mechanisms are altered in multiple stages of the atherosclerotic process. Apolipoprotein E deficient mice (ApoE /-), a mouse model of atherosclerosis, and their wild-type (WT) counterparts were used to assess agonist-stimulated synthesis of prostacyclin (PGI2), inhibition of platelet aggregation ex vivo and intra-platelet cAMP levels. Furthermore, pilot studies with of altered platelet reactiveness in a familial hypercholesterolemia patient were performed. Basal U46619 and ADP -induced platelet aggregation in vitro were increased in ApoE-/- mice at 18-20 weeks in comparison to 8 10 weeks of age. Systemically administered endothelin-1 (ET 1) or bradykinin (BK) inhibited platelet aggregation in a similar fashion in 8-10 week-old ApoE-/- and WT mice, but not in the ApoE-/- mice at 18 20 weeks of age, although both peptides maintained their capacity to increase plasma levels of the PGI2. Intravenous infusion of PGI2 also failed to inhibit platelet aggregation ex vivo in 18-20 week old ApoE /- mice. Familial hypercholesterolemic platelets also showed reduced platelet inhibition with a direct anti-platelet mechanism, Liver X Receptor (LXR) agonism. Interestingly, both BK and PGI2 retained their ability to increase intra-platelet cAMP in WT and ApoE-/- mice. Our results suggest that a loss of activity of endogenous inhibitory mechanisms could contribute to the increased platelet reactivity in hypercholesterolemia and that this phenomenon occurs early in the atherosclerotic process.

06 - ALTERED INHIBITION OF PLATELET AGGREGATION IN HYPERCHOLEROLEMIA IN MICE AND HUMANS