Edoxaban improves venous thrombosis via increasing hydrogen sulfde and homocysteine in rat model

Abstract

Anticoagulant therapy is prescribed to millions of patients worldwide for the prevention and treatment of venous thrombosis. Evidence has indicated that edoxaban is a potential drug of oral anticoagulant in the acute treatment of venous thromboembolism. Hydrogen sulfde and homocysteine plasma concentration are indicators of cardiovascular and neuro-vascular disease risk factors that have attracted considerable attention for regulation of vascular health and homeostasis. However, the molecular mechanism of edoxaban-mediated differences of hydrogen sulfide and homocysteine has not been investigated in the progression of venous thrombosis. In the present study, the authors analyzed the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in the vein endothelial cells and expression levels of hydrogen sulfide and homocysteine. Homocysteine-hydrogen sulfide metabolism through transsulfuration and that transsulfura-tion capacity and hydrogen sulfide availability have been investigated both in vitro and in vivo following treatment with edoxaban. Matrix metalloproteinase (MMP) activation and cystathionine β-synthase (CBS) and cystathionine γ-lyase (CGL) levels were studied in a cell model and rat model of vein thrombosis prior and post treatment of edoxaban. The therapeutic effects of edoxaban for rats with vein thrombosis were determined by clinical diagnose scores. The results demonstrated that edoxaban increased expression levels of hydrogen sulfde and homocysteine in microvascular endothe-lial cells. It was observed that the transsulfuration enzymes, CBS and CGL levels were upregulated in murine microvas-cular endothelial cells. The MMP-9 expression level and activity and homocysteine-hydrogen sulfde metabolism were increased in murine microvascular endothelial cells following edoxaban treatment. In addition, CBS and CGL activities were upregulated in murine microvascular endothelial cells and a rat model of venous thrombosis following treatment with edoxaban. Furthermore, it was observed that edoxaban increased PI3K and AKT expression both in vitro and in vivo. In addition, edoxaban significantly improved endothelial injury and inhibited thrombosis factors expression in rat model of venous thrombosis. In conclusion, these findings suggested that edoxaban can improve venous thrombosis by decreasing hydrogen sulfde and homocysteine through the PI3K/AKT signaling pathway.