Advances in vascular thiol isomerase function.
Advances in vascular thiol isomerase function.
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DOI：
10.1097/moh.0000000000000362
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发表时间：
2017-09
影响因子：
3.2
通讯作者：
Flaumenhaft R
中科院分区：
文献类型：
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作者：
Flaumenhaft R
本文就血管硫醇异构酶功能研究的最新进展作一综述。最初观察到蛋白二硫异构酶（PDI）在血栓形成中的作用发生在大约十年前。当时，人们对PDI或其他血管硫醇异构酶如何促进血栓形成知之甚少。虽然这个问题还远未解决，但过去几年在几个领域取得了实质性进展，本文将对此进行回顾。(1)研究了PDI结构与其功能之间的关系，并将其应用于确定对血栓形成至关重要的PDI结构域。(2)研究了巯基异构酶在血小板和内皮细胞中直接储存和释放的机制。(3)包括动力学捕获在内的新技术已经确定了血管硫醇异构酶在血栓形成过程中修饰的底物。(4)巯基异构酶的新型抑制剂已经被开发出来，这些抑制剂既可以作为询问PDI功能的工具，也可以作为潜在的治疗药物。(5)已经进行了人体研究，以测量疾病状态下循环中的PDI，并评估口服PDI抑制剂对体外凝血酶生成的影响。目前的研究结果表明，巯基异构酶介导的受体和血浆蛋白中的二硫键修饰是控制血栓形成和血管功能的一个重要层面。
This review will provide an overview of several recent advances in the field of vascular thiol isomerase function. The initial observation that protein disulfide isomerase (PDI) functions in thrombus formation occurred approximately a decade ago. At the time, there was little understanding regarding how PDI or other vascular thiol isomerases contribute to thrombosis. While this problem is far from solved, the past few years have seen substantial progress in several areas that will be reviewed in this article. (1) The relationship between PDI structure and its function has been investigated and applied to identify domains of PDI that are critical for thrombus formation. (2) The mechanisms that direct thiol isomerase storage and release from platelets and endothelium have been studied. (3) New techniques including kinetic-based trapping have identified substrates that vascular thiol isomerases modify during thrombus formation. (4) Novel inhibitors of thiol isomerases have been developed that are useful both as tools to interrogate PDI function and as potential therapeutics. (5) Human studies have been conducted to measure circulating PDI in disease states and evaluate the effect of oral administration of a PDI inhibitor on ex vivo thrombin generation. Current findings indicate that thiol isomerase-mediated disulfide bond modification in receptors and plasma proteins is an important layer of control of thrombosis and vascular function more generally.