LAUSR

Diabetes is a global health problem, affecting 382 million people worldwide. Critically, up to 70% of deaths from diabetes are due to the development of occlusive blood clots (thrombosis), leading to heart attack and stroke. This is due to both accelerated atherosclerosis and an exaggerated thrombotic response. Platelets are central to the initiation and promotion of thrombus formation. Importantly, in diabetic individuals these cells are ‘hyperactive’ resulting in larger, more occlusive thrombi. Moreover, currently used anti-platelet agents have reduced efficacy in diabetic patients. The underlying mechanisms responsible for platelet hyperactivity and antiplatelet resistance in diabetes is incompletely understood. Our recent work has uncovered a new mechanism of enhanced platelet aggregation and adhesion in diabetes, which is mediated by biomechanical activation of the major platelet integrin, GPIIb-IIIa. How diabetes promotes enhanced sensitivity to biomechanical stimuli in GPIIb-IIIa is an important remaining question. Chronic oxidative stress is a well-defined risk factor for cardiovascular disease and diabetes. Herein, we explored the possibility that chronic oxidative stress may promote redox-mediated modifications of GPIIb-IIIa in diabetic platelets. The reduction/oxidation state of cysteines in GPIIb-IIIa have been reported to mediate the conformation, and thus ligand binding affinity, of this adhesion receptor. Here we employed multiple techniques to probe the redox state of these cysteines to understand whether chronic oxidative stress can post-translationally modify GPIIb-IIIa to account for the increased reactivity of this integrin in diabetic platelets. Understanding the role of oxidative stress in modifying the platelet integrin GPIIb-IIIa could have important implications in how we approach developing strategies to treat platelet hyperactivity in diabetes.