Thiol isomerases in thrombus formation.
Thiol isomerases in thrombus formation.
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DOI：
10.1161/circresaha.114.301808
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发表时间：
2014-03-28
影响因子：
20.1
通讯作者：
Flaumenhaft R
中科院分区：
文献类型：
--
作者：
Furie B;Flaumenhaft R
蛋白二硫异构酶，ERp5和ERp57，在其他巯基异构酶中，对于血栓形成的起始很重要。采用小鼠激光损伤血栓形成模型诱导体内动脉血栓形成，结果表明血栓形成与血小板分泌PDI有关，抑制PDI可阻断血小板血栓形成和纤维蛋白生成，内皮细胞活化导致PDI分泌。使用该模型和其他小鼠血栓形成模型的类似结果证明了ERp5和ERp57在血栓形成起始中的重要性。整合素αIIbβ3和αVβ3在这一过程中发挥关键作用，并直接与PDI、ERp5和ERp57相互作用。巯基异构酶参与血栓形成的机制正在通过诱捕突变形式进行评估，以确定参与连接巯基异构酶、血小板受体激活和纤维蛋白生成的网络途径的巯基异构酶的底物。利用异槲皮素和槲皮素- 3-芦丁苷，通过高通量筛选鉴定出PDI抑制剂，正在探索蛋白二硫异构酶作为抗血栓的靶点。巯基异构酶的表达调控、巯基异构酶的储存和分泌分析以及电子传递途径的确定是理解这一新发现的血栓形成起始调控机制的关键问题。
Protein disulfide isomerase, ERp5 and ERp57, among perhaps other thiol isomerases, are important for the initiation of thrombus formation. Using the laser injury thrombosis model in mice to induce in vivo arterial thrombus formation, it was shown that thrombus formation is associated with PDI secretion by platelets, that inhibition of PDI blocked platelet thrombus formation and fibrin generation, and that endothelial cell activation leads to PDI secretion. Similar results using this and other thrombosis models in mice have demonstrated the importance of ERp5 and ERp57 in the initiation of thrombus formation. The integrins αIIbβ3 and αVβ3 play a key role in this process and interact directly with PDI, ERp5 and ERp57. The mechanism by which thiol isomerases participate in thrombus generation is being evaluated using trapping mutant forms to identify substrates of thiol isomerases that participate in the network pathways linking thiol isomerases, platelet receptor activation and fibrin generation. Protein disulfide isomerase as an antithrombotic target is being explored using isoquercetin and quercetin 3-rutinoside, inhibitors of PDI identified by high throughput screening. Regulation of thiol isomerase expression, analysis of the storage and secretion of thiol isomerases and determination of the electron transfer pathway are key issues to understanding this newly discovered mechanism of regulation of the initiation of thrombus formation.