title: Oxidative stress-related mechanisms affecting response to aspirin in diabetes mellitus.
abstract: 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.
authors.affiliation: 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. Electronic address: f.santilli@unich.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.affiliation: 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.
authors.forename: Domenico
authors.initials: D
authors.lastname: Lapenna
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: La Barba
authors.affiliation: 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.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Davì
mesh_terms: D000449:Aldehyde Reductase / Q000378:metabolism; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D028441:F2-Isoprostanes / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000378:metabolism; D015539:Platelet Activation; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D013927:Thrombosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013928:Thromboxane A2 / Q000378:metabolism
chemical_list: D028441:F2-Isoprostanes; D008054:Lipid Peroxides; D010975:Platelet Aggregation Inhibitors; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D013928:Thromboxane A2; D000449:Aldehyde Reductase; D005947:Glucose; D001241:Aspirin
keywords: Aspirin responsiveness; Cardiovascular disease; Diabetes mellitus; Free radicals; Lipid peroxidation; Oxidative stress