De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin

Aspirin affords cardioprotection through the acetylation of serine(529) in human cyclooxygenase-1 (COX-1) of anucleated platelets, inducing a permanent defect in thromboxane A(2) (TXA(2))-dependent platelet function. However, heterogeneity of COX-1 suppression by aspirin has been detected in cardiovascular disease and may contribute to failure to prevent clinical events. The recent recognized capacity of platelets to make proteins de novo paves the way to identify new mechanisms involved in the variable response to aspirin. We found that in washed human platelets, the complete suppression of TXA(2) biosynthesis by aspirin, in vitro, recovered in response to thrombin and fibrinogen in a time-dependent fashion ( at 0.5 and 24 hours, TXB2 averaged 0.1 +/- 0.03 and 3 +/- 0.8 ng/mL; in the presence of arachidonic acid [10 mu mol/L], it was 2 +/- 0.7 and 25 +/- 7 ng/mL, respectively), and it was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol 3-kinase. The results that COX-1 mRNA was readily detected in resting platelets and that [S-35]-methionine was incorporated into COX-1 protein after stimulation strongly support the occurrence of de novo COX-1 synthesis in platelets. This process may interfere with the complete and persistent suppression of TXA(2) biosynthesis by aspirin necessary for cardioprotection.