THE PHARMACOLOGY OF ASPIRIN

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

Acting as an antiplatelet drug, aspirin substantially reduces the occurrence of myocardial infarction and stroke.[unreadable] Despite its remarkable efficacy, some patients do not respond to the drug, raising the question of whether they are[unreadable] resistant its antiplatelet action. This proposal addresses the interindividual variation in the effect of aspirin. Aspirin[unreadable] inhibits prostaglandin H synthase-1 (PGHS-1) by acetylating Ser530 in the catalytic site, thereby irreversibly[unreadable] inhibiting formation of thromboxane A2, an agonist for platelet aggregation. We present novel evidence that[unreadable] acetylation of the PGH synthases by aspirin is highly regulated by the oxidative state of the enzymes; elevation of[unreadable] peroxide concentration antagonizes acetylation, suggesting that it may require hydrogen bonding of aspirin to[unreadable] Tyr385. As Tyr385 is converted to a radical by PGHS peroxidase activity, we propose to examine the participation[unreadable] of PGHS peroxidase activity in the peroxide-induced reversal of acetylation and to characterize the binding of[unreadable] aspirin in the catalytic site with crystallography to ascertain its position in relation to Tyr385. Extending this finding[unreadable] to patients, we will investigate clinical states, including the metabolic syndrome, that are associated with increased[unreadable] hydroperoxide formation and aspirin resistance. The biomarkers that have been associated with aspirin resistance[unreadable] will be evaluated and new metrics for aspirin's effect on its molecular target examined. High levels of excretion of[unreadable] the thromboxane metabolite, 11 -dehydro-thromboxane B2 (TxM), have been associated with an increased risk of[unreadable] coronary events. We now have evidence that a significant portion of TxM in cigarette smokers derives from an[unreadable] extra-platelet source via the inducible PGHS-2 pathway, implying an inflammatory cell origin. The extent to which[unreadable] extra-platelet PGHS-2 derived TxM contributes to high levels of TxM in patients with coronary disease will be[unreadable] determined and correlated with the PGHS-2 promoter polymorphism, with clinical characteristics, and with[unreadable] inflammatory markers. We have found that the initial inhibition of ADP-induced aggregation by aspirin is lost over[unreadable] weeks of treatment. Proposed studies will determine whether this loss of effect of aspirin is dose-dependent, and[unreadable] will further characterize the changes in platelet function associated with the time-dependent loss of effect, including[unreadable] an analysis of changes in platelet protein expression.