Vascular thiol isomerases in thrombosis: The yin and yang.
Vascular thiol isomerases in thrombosis: The yin and yang.
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DOI：
10.1111/jth.15019
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发表时间：
2020-11
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影响因子：
--
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中科院分区：
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--
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近年来，以血管硫醇异构酶为代表的胞外蛋白二硫键异构酶研究取得了长足的进展。蛋白二硫键异构酶(PDI)家族的四个成员，即PDI、ERp57、ERp72和ERp5，被证明是由血管损伤部位的活化的血小板和内皮细胞分泌的。每种异构酶单独支持血小板聚集和凝血，多水平的证据表明，包括抑制性抗体、靶向基因敲除小鼠和突变异构酶。跨膜PDI家族成员TMX1最近被证明具有抑制血小板功能和血栓形成的作用，表明PDI在血栓形成中具有相反的功能。这些观察提供了一个新的概念，即硫醇异构酶既可以正向调节止血，也可以负向调节止血，构成控制止血因子激活的OFF-ON氧化还原开关。这个氧化还原网络用来维持血管的动态平衡。血小板上的整合素，如αIIbβ3纤维蛋白原受体似乎是主要的底物，另一种底物是von Willebrand因子的血小板受体，即糖蛋白Ibα。血栓形成前的PDI的S亚硝化可能还会对血小板和血栓形成产生负面调节作用。硫醇异构酶也调节小鼠模型的凝血，口服PDI抑制剂异槲皮素的临床试验显著降低了血栓形成风险患者的凝血标志物。这篇综述更新了该领域的最新发现，并提出了新的证据，即血栓前分泌的PDI介导的基于硫醇/二硫键的反应由该家族的跨膜成员TMX1平衡。
There has recently been considerable progress of the field of extracellular protein disulfide isomerases with vascular thiol isomerases in the forefront. Four members of protein disulfide isomerase (PDI) family of enzymes, PDI, ERp57, ERp72, and ERp5, have been shown to be secreted from activated platelets and endothelial cells at the site of vascular injury. Each isomerase individually supports platelet accumulation and coagulation, as indicated by multiple levels of evidence, including inhibitory antibodies, targeted knockout mice, and mutant isomerases. The transmembrane PDI family member TMX1 was recently shown to inhibit platelet function and thrombosis, demonstrating that the PDIs can have opposing functions in thrombosis. These observations provide a new concept that thiol isomerases can both positively and negatively regulate hemostasis, constituting off-on redox switches controlling activation of hemostatic factors. This redox network serves to maintain vascular homeostasis. Integrins such as the αIIbβ3 fibrinogen receptor on platelets appear to be major substrates, with the platelet receptor for von Willebrand factor, glycoprotein Ibα, as another substrate. S-nitrosylation of the prothrombotic PDIs may additionally negatively regulate platelets and thrombosis. Thiol isomerases also regulate coagulation in mouse models, and a clinical trial with the oral PDI inhibitor isoquercetin substantially decreased markers of coagulation in patients at risk for thrombosis. This review updates recent findings in the field and addresses emerging evidence that thiol/disulfide-based reactions mediated by the prothrombotic secreted PDIs are balanced by the transmembrane member of this family, TMX1.
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影响因子：
2.9
作者：
Essex, DW;Miller, A;Feinman, RD
通讯作者：
Feinman, RD
影响因子：
3.2
作者：
Essex DW;Wu Y
通讯作者：
Wu Y
DOI：
10.1161/atvbaha.116.307461
发表时间：
2016-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Crescente M;Pluthero FG;Li L;Lo RW;Walsh TG;Schenk MP;Holbrook LM;Louriero S;Ali MS;Vaiyapuri S;Falet H;Jones IM;Poole AW;Kahr WH;Gibbins JM
通讯作者：
Gibbins JM
DOI：
10.1111/jth.13302
发表时间：
2016-05
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Bye AP;Unsworth AJ;Gibbins JM
通讯作者：
Gibbins JM
DOI：
10.1111/jth.14291
发表时间：
2018-11
期刊：
Journal of thrombosis and haemostasis : JTH
影响因子：
--
作者：
Bekendam RH;Iyu D;Passam F;Stopa JD;De Ceunynck K;Muse O;Bendapudi PK;Garnier CL;Gopal S;Crescence L;Chiu J;Furie B;Panicot-Dubois L;Hogg PJ;Dubois C;Flaumenhaft R
通讯作者：
Flaumenhaft R