Santilli Francesca, Lapenna Domenico, La Barba Sara, Davì Giovanni
Center of Excellence on Aging, "G. d'Annunzio" University Foundation, and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, 66013 Chieti, Italy.
Center of Excellence on Aging, "G. d'Annunzio" University Foundation, and Department of Medicine and Aging, University of Chieti "G. d'Annunzio" School of Medicine, 66013 Chieti, Italy.
Free Radic Biol Med. 2015 Mar;80:101-10. doi: 10.1016/j.freeradbiomed.2014.12.010. Epub 2014 Dec 18.
Type 2 diabetes mellitus (T2DM) is a major cardiovascular risk factor. Persistent platelet activation plays a key role in atherothrombosis in T2DM. However, current antiplatelet treatments appear less effective in T2DM patients vs nondiabetics at similar risk. A large body of evidence supports the contention that oxidative stress, which characterizes DM, may be responsible, at least in part, for less-than-expected response to aspirin, with multiple mechanisms acting at several levels. This review discusses the pathophysiological mechanisms related to oxidative stress and contributing to suboptimal aspirin action or responsiveness. These include: (1) mechanisms counteracting the antiplatelet effect of aspirin, such as reduced platelet sensitivity to the antiaggregating effects of NO, due to high-glucose-mediated oxidative stress; (2) mechanisms interfering with COX acetylation especially at the platelet level, e.g., lipid hydroperoxide-dependent impaired acetylating effects of aspirin; (3) mechanisms favoring platelet priming (lipid hydroperoxides) or activation (F2-isoprostanes, acting as partial agonists of thromboxane receptor), or aldose-reductase pathway-mediated oxidative stress, leading to enhanced platelet thromboxane A2 generation or thromboxane receptor activation; (4) mechanisms favoring platelet recruitment, such as aspirin-induced platelet isoprostane formation; (5) modulation of megakaryocyte generation and thrombopoiesis by oxidative HO-1 inhibition; and (6) aspirin-iron interactions, eventually resulting in impaired pharmacological activity of aspirin, lipoperoxide burden, and enhanced generation of hydroxyl radicals capable of promoting protein kinase C activation and platelet aggregation. Acknowledgment of oxidative stress as a major contributor, not only of vascular complications, but also of suboptimal response to antiplatelet agents in T2DM, may open the way to designing and testing novel antithrombotic strategies, specifically targeting oxidative stress-mediated mechanisms of less-than-expected response to aspirin.
2型糖尿病（T2DM）是主要的心血管危险因素。持续性血小板活化在T2DM的动脉粥样硬化血栓形成中起关键作用。然而，与具有相似风险的非糖尿病患者相比，目前的抗血小板治疗在T2DM患者中似乎效果较差。大量证据支持以下观点：以糖尿病为特征的氧化应激可能至少部分导致了对阿司匹林的反应低于预期，多种机制在多个层面发挥作用。本综述讨论了与氧化应激相关的病理生理机制，这些机制导致阿司匹林作用或反应性欠佳。其中包括：（1）抵消阿司匹林抗血小板作用的机制，例如由于高糖介导的氧化应激导致血小板对一氧化氮抗聚集作用的敏感性降低；（2）干扰COX乙酰化的机制，尤其是在血小板水平，例如脂质过氧化氢依赖性地损害阿司匹林的乙酰化作用；（3）促进血小板预激活（脂质过氧化氢）或激活的机制（F2-异前列腺素，作为血栓素受体的部分激动剂），或醛糖还原酶途径介导的氧化应激，导致血小板血栓素A2生成增加或血栓素受体激活；（4）促进血小板募集的机制，例如阿司匹林诱导的血小板异前列腺素形成；（5）通过氧化HO-1抑制调节巨核细胞生成和血小板生成；以及（6）阿司匹林-铁相互作用，最终导致阿司匹林的药理活性受损、脂质过氧化物负荷增加以及能够促进蛋白激酶C激活和血小板聚集的羟基自由基生成增加。认识到氧化应激不仅是血管并发症的主要促成因素，也是T2DM中对抗血小板药物反应欠佳的主要促成因素，可能为设计和测试新的抗血栓策略开辟道路，这些策略专门针对氧化应激介导的对阿司匹林反应低于预期的机制。
