Platelet Isoprostane Overproduction in Diabetic Patients Treated With Aspirin

Abstract

Aspirin modestly influences cardiovascular events in patients with type 2 diabetes mellitus (T2DM), but the reason is unclear. The aim of the study was to determine whether in T2DM patients aspirin enhances platelet isoprostanes, which are eicosanoids with proaggregating properties derived from arachidonic acid oxidation by platelet NOX2, the catalytic subunit of reduced NAD phosphate oxidase. A cross-sectional study was performed comparing T2DM patients, treated (n = 50) or not treated (n = 50) with 100 mg/day aspirin, with 100 nondiabetic patients, matched for age, sex, atherosclerosis risk factors, and aspirin treatment. A short-term (7 days) treatment with 100 mg/day aspirin also was performed in 36 aspirin-free diabetic and nondiabetic patients. Higher platelet recruitment, platelet isoprostane, and NOX2 activation was found in diabetic versus nondiabetic patients and in aspirin-treated diabetic patients versus nontreated patients (P < 0.001). Platelet thromboxane (Tx) A2 (P < 0.001) was inhibited in all aspirin-treated patients. In the interventional study, aspirin similarly inhibited platelet TxA2 in diabetic and nondiabetic patients (P < 0.001). Platelet recruitment, isoprostane levels, and NOX2 activation showed a parallel increase in diabetic patients (P < 0.001) and no changes in nondiabetic patients. These findings suggest that in aspirin-treated diabetic patients, oxidative stress–mediated platelet isoprostane overproduction is associated with enhanced platelet recruitment, an effect that mitigates aspirin-mediated TxA2 inhibition.

Clinical Application of NOX Activity and Other Oxidative Biomarkers in Cardiovascular Disease: A Critical Review

“…In another study, Davi et al demonstrated that in obese patients, 10% weight loss was associated with a significant reduction of F2-IsoP (30). Due to the role of NADPH oxidase as an enzymatic pathway generating F2-IsoP, we analyzed the interplay between the two variables in patients with obesity or diabetes (22,86). In both settings, we found a coincidental overexpression of NADPH oxidase and isoprostanes with a significant correlation between them, suggesting that in patients at a risk of atherosclerosis, the increase of isoprostanes is partly dependent on NADPH oxidase activation.…”

“…Such interplay is useful to explain the tendency to venous and artery thrombosis in clinical settings, such as heart failure, cirrhosis, anoxia-reoxygenation, atrial fibrillation, and diabetes, all of which are characterized by the up-regulation of NOX2 and the over-expression of isoprostane (10,11,(20)(21)(22).…”

Statins as Antithrombotic Drugs

“…23,34,35 Overgeneration of platelet nitric oxide is another mechanism that accounts for the antiplatelet effect of statins. Because of the negative effect of oxidative stress on nitric oxide biosynthesis and activity, 36 the impaired activation of NOX2-derived oxidative stress is likely to affect nitric oxide generation. Statins act by (1) inhibiting tissue factor synthesis and increasing thrombomodulin formation via inhibition of geranylgeranylation of the Rho/Rho kinase pathway and, in turn, nuclear factor-κB (NF-kB) activity; (2) increasing Kruppel-like factor 2 (KLF2) expression and endothelial nitric oxide synthase (eNOS) activity; (3) inhibiting oxidized low-density lipoprotein (oxLDL)-mediated CD36 and Toll-like receptor 4/6 (TLR4/6) activation; and (4) enhancing fibrinolysis.…”

“…23 The association of statins with aspirin could be investigated in clinical settings in which the clinical usefulness of statins has never been explored, such as acute ischemic stroke, or in settings at risk of atherosclerotic complication, such as diabetes mellitus, in which the clinical efficacy of aspirin is less than expected. 36 An association between statins and aspirin would be of particular interest because statins could counteract the upregulation of isoprostanes elicited by aspirin in patients with type 2 diabetes mellitus. 36 Treatment of acute venous thrombosis or prevention of venous thrombosis recurrence in patients at risk may be another attractive setting in which the antithrombotic property of statins may become useful clinically.…”

“…36 An association between statins and aspirin would be of particular interest because statins could counteract the upregulation of isoprostanes elicited by aspirin in patients with type 2 diabetes mellitus. 36 Treatment of acute venous thrombosis or prevention of venous thrombosis recurrence in patients at risk may be another attractive setting in which the antithrombotic property of statins may become useful clinically. 23,61 Given that inhibition of platelet TxA 2 prevents thrombosis recurrence in patients with previous deep venous thrombosis 61 and that statins inhibit not only platelet TxA 2 but also thrombin generation, interventional trials exploring the association between statins and aspirin to prevent thrombosis recurrence in deep venous thrombosis may be of interest.…”