THE PHARMACOLOGY OF ASPIRIN

作为一种抗血小板药物，阿司匹林大大减少了心肌梗死和中风的发生。 尽管疗效显著，但有些患者对这种药物没有反应，这就提出了一个问题，即他们是否 抵抗其抗血小板作用。这一建议涉及阿司匹林作用的个体差异。阿司匹林 通过乙酰化催化位点的Ser530抑制前列腺素H合酶-1（PGHS-1），从而不可逆地 抑制血栓素A2的形成，血栓素A2是血小板聚集的激动剂。我们提出了新的证据， 阿司匹林对PGH脱氢酶的乙酰化作用受酶的氧化状态高度调节; 过氧化氢浓度拮抗乙酰化，这表明它可能需要阿司匹林的氢键， Tyr 385.由于Tyr385被PGHS过氧化物酶活性转化为自由基，我们建议检查参与 的PGHS过氧化物酶活性在过氧化物诱导的乙酰化逆转，并表征结合 阿司匹林在催化位点与晶体学，以确定其位置的Tyr385。扩展这一发现 对于患者，我们将调查临床状态，包括代谢综合征，与增加的 氢过氧化物形成和阿司匹林抵抗。与阿司匹林抵抗相关的生物标志物 将进行评估，并检查阿司匹林对其分子靶点的影响的新指标。高水平的排泄 血栓烷代谢物，11-脱氢-血栓烷B2（TxM），与增加的 冠心病事件我们现在有证据表明，吸烟者体内的TxM很大一部分来自于 血小板外来源通过诱导型PGHS-2途径，这意味着炎症细胞来源。的程度 血小板外PGHS-2衍生的TxM有助于冠心病患者的高水平TxM， 确定并与PGHS-2启动子多态性、临床特征和 炎症标志物。我们已经发现阿司匹林对ADP诱导的聚集的初始抑制作用随着时间的推移而丧失。 数周的治疗。拟议的研究将确定阿司匹林的这种作用丧失是否是剂量依赖性的， 将进一步表征与时间依赖性效应丧失相关的血小板功能变化，包括 血小板蛋白表达变化的分析。

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