Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease.
Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease.
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DOI：
10.1161/atvbaha.114.303410
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Zwicker JI
中科院分区：
文献类型：
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作者：
Flaumenhaft R;Furie B;Zwicker JI
血栓形成的研究越来越多地应用体内工具，如转基因小鼠和活体显微镜来评估血栓形成的分子和细胞机制。这种方法的几个意想不到的发现之一是发现蛋白质二硫键异构酶在血管损伤部位的血栓形成中发挥重要作用。在临床前研究中观察到，常见摄入的槲皮素类黄酮槲皮素-3-芸香苷可抑制蛋白质二硫键异构酶并阻止血栓形成，这为使用蛋白质二硫键异构酶拮抗剂作为抗血栓药物的临床试验奠定了基础。尽管蛋白质二硫键异构酶促进血小板活化和纤维蛋白形成的机制尚未阐明，但蛋白质二硫键异构酶拮抗剂目前正在开发作为抗血栓药物。本综述将考虑蛋白质二硫键异构酶在血小板聚集和纤维蛋白生成中的作用，重点关注在血栓形成的情况下阻断蛋白质二硫键异构酶活性的药理学策略。将考虑测试蛋白质二硫键异构酶抑制以降低血栓形成发生率的功效的潜在适应症和临床试验设计。
The study of thrombus formation has increasingly applied in vivo tools such as genetically modified mice and intravital microscopy to the evaluation of molecular and cellular mechanisms of thrombosis. Among several unexpected findings of this approach was the discovery that protein disulfide isomerase serves an essential role in thrombus formation at sites of vascular injury. The observation that the commonly ingested quercetin flavonoid, quercetin-3-rutinoside, inhibits protein disulfide isomerase and blocks thrombus formation in pre-clinical studies has set the stage for clinical trials using protein disulfide isomerase antagonists as antithrombotics. Even though the mechanisms by which protein disulfide isomerase facilitates platelet activation and fibrin formation have yet to be elucidated, protein disulfide isomerase antagonists are currently being developed as antithrombotics. This review will consider what is known about the role of protein disulfide isomerase in platelet accumulation and fibrin generation with a focus on pharmacological strategies for blocking protein disulfide isomerase activity in the context of thrombus formation. Potential indications and clinical trial design for testing the efficacy of protein disulfide isomerase inhibition to reduce the incidence of thrombosis will be considered.