Thromboembolism is a commonly observed condition in geriatrics that is caused by vascular endothelial injury, platelet activation, physiological coagulation processes, reduction of anticoagulant activity, decreased fibrinolytic activity and abnormal flow in the heart chamber, artery or vein. The protein C anticoagulant system serves a crucial role in anticoagulant therapy for the treatment of thromboembolism. Previous findings have suggested that edoxaban is an efficient oral anticoagulant in the acute treatment of venous thromboembolism. In the present study, the efficacy of edoxaban on thromboembolism induced by atrial fibrillation was investigated in a mouse model. Inflammatory factors interleukin (IL)-1, -4, -8 and tumor necrosis factor (TNF)-α were analyzed in the sera of mice with fibrillation induced by thromboembolism. Expression and activity of thymic stromal lymphopoietin (TSLP) and activated protein C resistance were investigated in platelets and vascular endothelial cells (VECs). TSLP-induced platelet viability, Wnt-β phosphorylation and integrin expression were analyzed in platelets. Furthermore, Wnt-β expression and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in VECs were analyzed. Results demonstrated that the expression levels of IL-1, -4, -8 and TNF-α were significantly downregulated in the sera of mice with fibrillation and thromboembolism following treatment with edoxaban (P<0.01). Furthermore, the expression levels of prostacyclin (PGI2), prostaglandin (PG)E2, PGD2 and PGF2α were significantly increased in the sera of experimental mice that received edoxaban therapy (P<0.01). Results also indicated that edoxaban significantly stimulated the protein expression of TSLP and activated Wnt-β phosphorylation and integrin expression in platelets (P<0.01). In addition, edoxaban therapy significantly upregulated the expression levels of PI3K and AKT, and subsequently increased the activity of protein C and S in VECs (P<0.01). Notably, edoxaban treatment improved atrial fibrillation and thromboembolism, as determined by pathological analysis. In conclusion, these results suggested that edoxaban elicited beneficial effects for mice with atrial fibrillation induced by thromboembolism through the regulation of the Wnt-β-induced PI3K/ATK-activated protein C system.

译文

血栓栓塞是老年病中常见的疾病,由血管内皮损伤,血小板活化,生理性凝血过程,抗凝活性降低,纤溶活性降低以及心腔,动脉或静脉血流异常引起。 C蛋白抗凝剂系统在抗凝剂治疗血栓栓塞的治疗中起着至关重要的作用。先前的研究结果表明,依多沙班在静脉血栓栓塞的急性治疗中是一种有效的口服抗凝剂。在本研究中,在小鼠模型中研究了依多沙班对房颤诱发的血栓栓塞的疗效。在血栓栓塞引起的原发性小鼠血清中分析了炎症因子白介素(IL)-1,-4,-8和肿瘤坏死因子(TNF)-α。胸腺基质淋巴细胞生成素(TSLP)的表达和活性以及活化的蛋白C抗性在血小板和血管内皮细胞(VEC)中进行了研究。分析了TSLP诱导的血小板生存力,Wnt-β磷酸化和整联蛋白表达。此外,分析了VEC中的Wnt-β表达和磷酸肌醇3-激酶(PI3K)/蛋白激酶B(AKT)信号传导途径。结果表明,在用依多沙班治疗后,患有纤颤和血栓栓塞的小鼠血清中IL-1,-4,-8和TNF-α的表达水平显着下调(P <0.01)。此外,在接受edoxaban治疗的实验小鼠的血清中,前列环素(PGI2),前列腺素(PG)E2,PGD2和PGF2α的表达水平显着升高(P <0.01)。结果还表明,依多沙班显着刺激了血小板中TSLP的蛋白表达,并激活了Wnt-β磷酸化和整联蛋白的表达(P <0.01)。此外,edoxaban治疗显着上调了PI3K和AKT的表达水平,并随后增加了VEC中C和S蛋白的活性(P <0.01)。值得注意的是,根据病理分析确定,依多沙班治疗改善了心房纤颤和血栓栓塞。总之,这些结果表明,edoxaban通过调节Wnt-β诱导的PI3K / ATK激活的蛋白C系统,对血栓栓塞引起的房颤小鼠产生了有益的作用。

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