Inhibition of platelet aggregation ex vivo is repressed in apolipoprotein E deficient mice

In the present study, we assessed whether the endogenous platelet inhibitory mechanisms are altered in the early to moderate 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 (PGI 2 ), inhibition of platelet aggregation ex vivo, and intra-platelet cAMP levels. Basal U46619 and ADP -induced platelet aggregation in vitro were increased in ApoE−/− mice at 18–20 weeks in comparison with 8–10 weeks of age. Systemically administered endothelin-1 (ET-1) or bradykinin (BK) inhibited platelet aggregation in a similar fashion in 8- to 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 PGI 2 . Intravenous infusion of PGI 2 also failed to inhibit platelet aggregation ex vivo in 18- to 20-week-old ApoE−/− mice. Interestingly, both BK and PGI 2 retained their ability to increase intraplatelet cAMP in WT and ApoE−/− mice. Our results suggest that a loss of activity of endogenous inhibitorymechanisms could contribute to the increased platelet reactivity in ApoE−/− mice, and that this phenomenon occurs early in the intermediate stage of the atherosclerotic process.