Mitochondrial Oxidants Promote Platelet Activation and Thrombotic Susceptibility in Prediabetes

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Abstract

Recent studies suggest that prediabetes is an independent risk factor for cardiovascular thrombotic events. However, the mechanisms that may promote platelet activation and thrombosis in prediabetes remain elusive. To determine mechanisms linking prediabetes and thrombosis as a function of age, we recruited prediabetic and normoglycemic Veterans in young and middle-age groups. Compared to normoglycemic subjects, platelets from those with prediabetes exhibited increased activation, mitochondrial-oxidant load, mitochondrial-membrane hyperpolarization, and greater thrombus formation ex vivo regardless of age. Preincubation of platelets with mitochondria targeted antioxidants such as superoxide dismutase (SOD) mimetic or Mito quinol (MitoQ), rescued this prothrombotic phenotype. These phenotypes were recapitulated in C57BL6/J mice exhibiting early onset of glucose intolerance when fed high fat (HF) diet for two weeks. Treatment of HF-fed mice with a SOD-mimetic or MitoQ, or genetic overexpression of catalase within mitochondria, not only lowered mitochondrial-oxidants, hyperpolarization, Ca2+ levels and platelet activation, but also protected against increased potential for carotid and pulmonary thrombosis. We also observed a bidirectional regulation of platelet activation by Ca2+ and mitochondrial oxidants. These findings support the idea that mitochondrial-oxidant dependent platelet activation induces a prothrombotic state in clinical prediabetes and preclinical models of short-term glucose intolerance and can be reversed by mitochondria-targeted antioxidants.

Authors

Azaj Ahmed, Pooja Yadav, Melissa Jensen, Katharine Geasland, Jagadish S. Swamy, Douglas R. Spitz, E. Dale Abel, Diana Jalal, Sanjana Dayal