Role of redox-sensitive signalling pathways linked to GPIIb-IIIa in platelet hyperactivity and thrombosis in diabetes

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Diabetes has become one of the major healthcare challenges of the 21st century and a leading cause of cardiovascular disease worldwide. Up to 70% of all diabetes-related deaths are due to cardiovascular disease, primary related to atherothrombosis. Diabetes enhances the atherosclerotic process in large arteries, increasing the risk of acute myocardial infarction, ischemic stroke and peripheral disease. In addition to developing more extensive atherosclerosis, diabetic individuals also exhibit a prothrombotic phenotype that manifest as an exaggerated accumulation of platelets at sites of plaque disruption. However, the mechanisms by which diabetes causes platelet hyperactivity and a prothrombotic phenotype remain incompletely understood. The Jackson laboratory (host institute) recently defined a new mechanism promoting arterial thrombus formation that involves biomechanical (rheology-dependent) platelet activation that leads to aggregation of discoid platelets. Preliminary data show evidence that this aggregation mechanism is dysregulated in diabetes, leading to excessive discoid platelet aggregation and thrombus formation in vivo. Oxidative stress seems to have a key role in amplifying discoid platelet aggregation in diabetes by altering the shear-sensitivity of the major platelet adhesion receptor αIIbβ3 (commonly referred to as GPIIb-IIIa). The hypothesis of this project is that this biomechanical prothrombotic mechanism is associated with alterations in redox-sensitive signal pathways linked to GPIIb-IIIa. Importantly, exaggerated platelet aggregation is not inhibited by conventional antiplatelet agents such as aspirin and clopidogrel, which may partly explain reduced efficacy of antithrombotic therapy in individual with diabetes. The specific aim in this proposal is to examine whether inhibiting platelet redox-sensitive signalling pathways reduces platelet hyperactivity and thrombosis in diabetes. To address the question the functional impact of several signalling inhibitors linked to GPIIb-IIIa activation on shear-dependent adhesion of diabetic platelets will be investigated by several in vitro approaches. Pharmacological inhibitors that are highly effective in vitro, will be examined for their ability to inhibit shear-dependent discoid platelet aggregation in vivo, using several thrombosis mouse models. Results of this project could help to identify entirely new approaches to reduce the prothrombotic function of diabetes.