OPA1 A Novel Regulator of Sex-Dependent Differences in Thrombosis

OPA1 A Novel Regulator of Sex-Dependent Differences in Thrombosis

1. E. Dale Abel MD PhD, Carver College of Medicine, University of Iowa

Thrombosis is a major concern in: premenopausal females on oral contraceptives, menopausal women undergoing hormone replacement therapy, post-menopausal women and transgender individuals receiving estrogen supplementation. The mechanisms linking estrogen exposure with increased thrombosis risk is incompletely understood. Analysis of platelet transcripts in the Framingham cohort identified Optic atrophy 1 (OPA1) expression as being highly predictive of female sex and correlating with increased risk of diabetes and cardiovascular disease. OPA1 regulates mitochondrial fusion, electron transport chain (ETC), complex assembly, cristae morphology and apoptosis. To determine the functional relationship between platelet OPA1 expression and platelet function in relation to sex steroids we generated mice with platelet specific deletion of OPA-1 protein (pOPA1KO). Male pOPA1KO exhibited structurally and functionally compromised mitochondria and a prothrombotic phenotype characterized by increased agonist-induced activation, shortened time to stable occlusion of the carotid artery in vivo by (rose Bengal) photochemical injury and were more prone to develop a thrombus following permanent ligation of the inferior vena cava. In contrast, female pOPA1KO mice had normal mitochondrial structure and function. Both agonist-induced platelet activation and thrombus formation was unchanged in pOPA1KO females. Paradoxically, pOPA-1 KO female mice had increased time to stable occlusion of the carotid artery as assessed by photochemical injury. When platelets from pOPA-1 KO or control males were transferred into females following depletion of endogenous platelets, the reconstituted male platelets acquired the phenotype of female pOPA-1 KO mice. Thus, the time to stable occlusion of the carotid artery following photochemical injury was increased. Similarly, reconstitution of male mice with female pOPA1KO platelets were no longer prothrombotic. Gonadectomized pOPA1KO males had an increased time to stable occlusion and gonadectomized female pOPA1KO no longer exhibited increased time to stable carotid artery occlusion. Eugonadal pOPA1KO male mice treated with estrogen exhibited the pOPA1KO female thrombotic phenotype, with increased time to stable occlusion relative to control males. OPA-1 levels were positively correlated with increased platelet aggregation and increased estrogen levels in third trimester pregnant human females. Together, these findings reveal a synergistic interaction between platelet OPA1 levels and estrogen to promote thrombosis.