From the Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
Circ Res. 2014 Mar 28;114(7):1162-73. doi: 10.1161/CIRCRESAHA.114.301808.
Protein disulfide isomerase (PDI), 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. PDI 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.
蛋白质二硫键异构酶（PDI）、ERp5 和 ERp57，以及其他可能的巯基异构酶，对于血栓形成的启动非常重要。利用小鼠激光损伤血栓形成模型诱导体内动脉血栓形成，研究表明血栓形成与血小板 PDl 的分泌有关，PDI 的抑制可阻断血小板血栓形成和纤维蛋白生成，内皮细胞的激活导致 PDI 的分泌。使用这种模型和其他在小鼠中的血栓形成模型进行的类似研究表明，ERp5 和 ERp57 在血栓形成的启动中非常重要。整合素αIIbβ3 和 αVβ3 在这个过程中起着关键作用，并与 PDI、ERp5 和 ERp57 直接相互作用。目前正在使用捕获突变体来评估巯基异构酶参与血栓生成的机制，以鉴定参与将巯基异构酶、血小板受体激活和纤维蛋白生成联系起来的网络途径的巯基异构酶的底物。通过高通量筛选发现的 PDI 抑制剂异槲皮苷和芦丁 3-鼠李糖苷，正在探索将 PDI 作为抗血栓靶点。巯基异构酶表达的调控、巯基异构酶的储存和分泌的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启动调控机制的关键问题。
