AKT2 regulates endothelial-mediated coagulation homeostasis and promotes intrathrombotic recanalization and thrombus resolution in a mouse model of venous thrombosis.
AKT2 regulates endothelial-mediated coagulation homeostasis and promotes intrathrombotic recanalization and thrombus resolution in a mouse model of venous thrombosis.
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在静脉血栓形成小鼠模型中，AKT2 调节内皮介导的凝血稳态并促进血栓内再通和血栓溶解。
DOI：
10.1007/s11239-020-02112-9
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发表时间：
2020
影响因子：
4
通讯作者：
Shen,YingH
中科院分区：
文献类型：
--
作者：
Xie,Wanmu;Zhang,Lin;Luo,Wei;Zhai,Zhenguo;Wang,Chen;Shen,YingH
静脉血栓栓塞（VTE）具有较高的发病率和死亡率风险。了解静脉血栓形成和消退的机制对于改善VTE管理至关重要。AKT 2激酶是血小板活化和动脉血栓形成所必需的。在这项研究中，我们研究了AKT 2在静脉血栓形成中的作用，在静脉血栓形成的小鼠模型诱导下腔静脉（IVC）结扎。我们观察到在野生型（WT）小鼠的IVC连接中诱导AKT 2表达。有趣的是，尽管Akt 2 −/−小鼠和WT小鼠之间IVC结扎后的初始血栓大小相似，但Akt 2 −/−小鼠IVC结扎后的血栓消退延迟。与WT小鼠的IVC结扎相比，Akt 2 −/−小鼠的IVC结扎显示血栓调节蛋白（TM）水平降低，组织因子（TF）、凋亡和坏死性凋亡水平升高。此外，Akt 2-/-小鼠结扎的IVC中的血栓内内皮细胞未能形成小血管，导致再通和血栓消退受损。在Akt 2 −/−小鼠结扎的IVC的血栓和静脉壁中，TGF-β信号激活和纤维化重塑增加。我们进一步研究了AKT 2介导的内皮细胞凝血因子调节，发现AKT的靶点叉头盒蛋白O 1（FOXO 1）增强TF并抑制TM表达。通过抑制FOXO 1，AKT 2抑制TF表达，同时增加TM表达。我们的研究结果表明，AKT 2可以保护内皮细胞免于细胞死亡，调节内皮介导的凝血稳态，并促进静脉血栓形成中血栓内再通和血栓消退。这些观察结果表明AKT 2在静脉血栓形成和消退中的动态作用。
Venous thromboembolism (VTE) carries a high risk of morbidity and mortality. Understanding the mechanisms of venous thrombus formation and resolution is critical for improving VTE management. AKT2 kinase is essential for platelet activation and arterial thrombosis. In this study, we examined the role of AKT2 in venous thrombosis in a mouse model of venous thrombosis induced by inferior vena cava (IVC) ligation. We observed an induction of AKT2 expression in the ligated IVC of wild-type (WT) mice. Interestingly, although the initial thrombus size of the ligated IVC was similar betweenAkt2−/−mice and WT mice, thrombus resolution was delayed in the ligated IVC ofAkt2−/−mice. Compared with the ligated IVC of WT mice, the ligated IVC ofAkt2−/−mice displayed decreased levels of thrombomodulin (TM) and increased levels of tissue factor (TF), apoptosis, and necroptosis. In addition, intrathrombotic endothelial cells in the ligated IVC ofAkt2−/−mice failed to form small vessels, resulting in impaired recanalization and thrombus resolution. TGF-β signaling activation and fibrotic remodeling were increased in the thrombus and vein wall of the ligated IVC ofAkt2−/−mice. We further investigated the AKT2-mediated regulation of coagulation factors in endothelial cells and found that forkhead box protein O1 (FOXO1), a target of AKT, enhanced TF and inhibited TM expression. By inhibiting FOXO1, AKT2 suppressed TF expression while increasing TM expression. Our findings indicate that AKT2 may protect endothelial cells against cell death, regulate endothelial-mediated coagulation homeostasis, and promote intrathrombotic recanalization and thrombus resolution in venous thrombosis. These observations suggest dynamic roles of AKT2 in venous thrombus formation and resolution.