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.
Mol Med Rep. 2017 Nov;16(5):7706-7714. doi: 10.3892/mmr.2017.7574. Epub 2017 Sep 21.
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.
抗凝治疗被全世界数以百万计的患者用于预防和治疗静脉血栓形成。有证据表明，依度沙班是一种有潜力的口服抗凝药物，可用于急性治疗静脉血栓栓塞症。硫化氢和同型半胱氨酸的血浆浓度是心血管和神经血管疾病危险因素的指标，它们在调节血管健康和稳态方面受到了相当大的关注。然而，依度沙班介导的硫化氢和同型半胱氨酸差异在静脉血栓形成进展中的分子机制尚未被研究。在本研究中，作者分析了静脉内皮细胞中的磷酸肌醇 3-激酶（PI3K）/蛋白激酶 B（AKT）信号通路以及硫化氢和同型半胱氨酸的表达水平。通过转硫途径以及转硫能力和硫化氢可用性，在体外和体内研究了依度沙班治疗后同型半胱氨酸-硫化氢代谢。在依度沙班治疗前后的静脉血栓形成的细胞模型和大鼠模型中研究了基质金属蛋白酶（MMP）的激活以及胱硫醚-β-合酶（CBS）和胱硫醚γ-裂合酶（CGL）的水平。通过临床诊断评分确定了依度沙班治疗大鼠静脉血栓形成的疗效。结果表明，依度沙班增加了微血管内皮细胞中硫化氢和同型半胱氨酸的表达水平。观察到在鼠微血管内皮细胞中转硫酶 CBS 和 CGL 水平上调。依度沙班处理后，鼠微血管内皮细胞中 MMP-9 的表达水平和活性以及同型半胱氨酸-硫化氢代谢增加。此外，CBS 和 CGL 活性在依度沙班处理后的鼠微血管内皮细胞和静脉血栓形成大鼠模型中上调。此外，观察到依度沙班在体外和体内均增加了 PI3K 和 AKT 的表达。此外，依度沙班显著改善了静脉血栓形成大鼠模型中的内皮损伤并抑制了血栓形成因子的表达。总之，这些发现表明，依度沙班可以通过 PI3K/AKT 信号通路降低硫化氢和同型半胱氨酸来改善静脉血栓形成。
