De novo synthesis of cyclooxygenase-1 counteracts the suppression of platelet thromboxane biosynthesis by aspirin.
Aspirin affords cardioprotection through the acetylation of serine529 in human cyclooxygenase-1 (COX-1) of anucleated platelets, inducing a permanent defect in thromboxane A2 (TXA2)-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 TXA2 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 micromol/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 [35S]-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 TXA2 biosynthesis by aspirin necessary for cardioprotection.
Consorzio Mario Negri Sud, Santa Maria Imbaro, Gabriele d'Annunzio University and Foundation, Chiety, Italy.
Virgilio
V
Evangelista
Stefano
S
Manarini
Angelo
A
Di Santo
Marta L
ML
Capone
Emanuela
E
Ricciotti
Luigia
L
Di Francesco
Stefania
S
Tacconelli
Andrea
A
Sacchetti
Sandra
S
D'Angelo
Antonio
A
Scilimati
Maria G
MG
Sciulli
Paola
P
Patrignani
D000328:Adult; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D013928:Thromboxane A2 / Q000096:biosynthesis*
D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D013928:Thromboxane A2; D051545:Cyclooxygenase 1; D019869:Phosphatidylinositol 3-Kinases; D001241:Aspirin