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

Song,Wei; Ci,Hongbo; Tian,Guanglei; Zhang,Yanjun; Ge,Xiaohu

doi:10.3892/mmr.2017.7574

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

Authors:
- Wei Song
- Hongbo Ci
- Guanglei Tian
- Yanjun Zhang
- Xiaohu Ge
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Affiliations: Postgraduate College of Xinjiang Medical University, Urumqi, Xinjiang 830054, P.R. China, Department of Vascular Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830011, P.R. China, Department of Clinical Medical Research Center, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang 830011, P.R. China
Published online on: September 21, 2017 https://doi.org/10.3892/mmr.2017.7574
Pages: 7706-7714

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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 sulfide and homocysteine plasma concentration are indicators of cardiovascular and neurovascular 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 transsulfuration 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 sulfide and homocysteine in microvascular endothelial cells. It was observed that the transsulfuration enzymes, CBS and CGL levels were upregulated in murine microvascular endothelial cells. The MMP‑9 expression level and activity and homocysteine‑hydrogen sulfide 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 sulfide and homocysteine through the PI3K/AKT signaling pathway.

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