Abstract 484: Platelet Specific Deletion of Opa-1 Reveals Gender Dimorphic Effects on Platelet Dysfunction and Thrombus Formation in Mice

Abstract

Diabetes Mellitus and its complications remains a major public health burden. Cardiovascular disease (CVD) is the leading cause of death amongst diabetics and disproportionally affects women. Thrombosis represents one of the primary underlying pathologies in CVD. However, the mechanisms by which platelet dysfunction develops in diabetics are unclear. Preliminary studies revealed enrichment in platelet-derived transcripts encoding the mitochondrial dynamics proteins optic atrophy (OPA)-in females and mitofusin-2, dynamin-related protein-1, and mitochondrial fission 1 protein in both genders collected from the Framingham Offspring cohort, suggesting that platelet dysfunction in the diabetic milieu might be related to abnormal mitochondrial dynamics. Thus to define the relationship between mitochondrial dynamics and platelet dysfunction/thrombosis we generated mice with platelet-specific deletion of OPA1, a protein that regulates mitochondrial fusion, electron transport complex (ETC) assembly and apoptosis. Deletion of OPA-1 in platelets reduced mitochondrial oxygen consumption by approximately 50 % and reduced mitochondrial ETC subunit expression in both genders. Hydrogen peroxide levels were reduced by 40% in females but increased by 20% in males. Unexpectedly, females exhibited a 10-fold increase in expression of the NADPH oxidase (NOX) subunits gp91phox and p47phox, whereas NOX was unchanged in males. The absence of OPA1 was associated with longer time to stable occlusion in females but with decreased time to stable occlusion in males as assessed in vivo by rose Bengal photochemical injury. Also, male OPA1 deficient mice, were more prone to develop a thrombus (14/15 knockouts vs. 4/8 controls) following permanent ligation of the inferior vena cava, but this increase in venous thrombosis was not observed in females mice. Taken together, these data suggest that increased OPA1 expression observed in females with diabetes could represent a critical pathophysiologic mechanism in diabetic females that could contribute to their disproportional increased relative risk of thrombosis. We also identify for the first time, an essential role for OPA1 in regulating platelet mitochondrial function, platelet activation and thrombosis.