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Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans.
口服 Bruton 酪氨酸激酶抑制剂选择性阻断人类动脉粥样硬化斑块触发的血栓形成。

摘要

Interaction of von Willebrand factor (VWF) with platelet glycoprotein Ib (GPIb) and interaction of collagen with GPVI are essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk), which can be blocked irreversibly by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long-term safety. We found that ibrutinib and the novel Btk inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid. Moreover, Btk inhibitors prevented platelet thrombus formation on human atherosclerotic plaque homogenate and plaque tissue sections from arterially flowing blood, whereas integrin α2β1 and VWF-dependent platelet adhesion to collagen, which is important for physiologic hemostasis, was not affected. This plaque-selective platelet inhibition was also observed in CLL patients taking 450 mg of ibrutinib and in volunteers after much lower and intermittent dosing of the drug. We conclude that Btk inhibitors, by targeting GPIb and GPVI signal transduction, suppress platelet thrombus accretion from flowing blood on atherosclerotic plaque but spare hemostatic platelet function. Btk inhibitors hold promise as the first culprit lesion-focused oral antiplatelet drugs and are effective at low doses.

译文

血管性血友病因子 (VWF) 与血小板糖蛋白 Ib (GPIb) 的相互作用以及胶原与 GPVI 的相互作用对于破裂或侵蚀的动脉粥样硬化斑块 (动脉粥样硬化血栓形成) 上的血栓形成至关重要。GPIb 和 GPVI 信号通过 Bruton 酪氨酸激酶 (Btk),可通过口服伊布替尼不可逆地阻断,伊布替尼是一种长期安全的慢性淋巴细胞白血病 (CLL) 的既定疗法。我们发现,ibrutinib 和新型 Btk 抑制剂 acalabrutinib 和 ONO/GS-4059 阻断暴露于人类斑块匀浆和胶原蛋白的血液中 GPVI 依赖性的静态血小板聚集,但不阻断 ADP 或花生四烯酸。此外,Btk 抑制剂阻止了人动脉粥样硬化斑块匀浆和动脉血流斑块组织切片上的血小板血栓形成,而整合素 α 2 β 1 和 VWF 依赖性血小板与胶原的粘附, 这对生理性止血很重要,不受影响。这种斑块选择性血小板抑制也在服用 450 毫克伊布替尼的 CLL 患者和服用该药物的志愿者中观察到。我们得出结论,Btk 抑制剂通过靶向 GPIb 和 GPVI 信号转导,抑制动脉粥样硬化斑块上流动血液中血小板血栓形成,但抑制止血血小板功能。Btk 抑制剂有望成为以病变为重点的口服抗血小板药物的第一罪魁祸首,并且在低剂量下有效。

bruton tyrosine kinase

肿瘤 慢性淋巴细胞性白血病 临床研究术语
概述  :  

布鲁顿酪氨酸激酶(BTK),即非受体酪氨酸激酶Tec家族的一个成员,是在除了T淋巴细胞和自然杀伤细胞之外的所有造血细胞类型中表达的关键信号酶。BTK在将细胞表面B细胞受体(BCR)刺激连接到下游细胞内应答的B细胞信号途径中发挥至关重要的作用。BTK是B细胞发育、激活、信号传导和存活的关键调节剂;另外,BTK在众多其它造血细胞信号途径中起作用,例如,巨噬细胞中Toll样受体(TLR)和细胞因子受体介导的TNF-α产生,肥大细胞中IgE受体(FceRI)的信号传导,B系淋巴样细胞中Fas/ΑΡ0

Bruton

释    义   n. (Bruton)人名;(英)布鲁顿;(法)布吕东

例    句   That year, I was giving the traditional Irish greeting, cad mle filte, a hundred thousand welcomes, to a new Irish prime minister, John Bruton, who was continuing the peace policy of his predecessor. 那一年,我给新任爱尔兰首相约翰.布鲁顿发出了“十万声欢迎”的爱尔兰传统祝福语,他正继续执行着前任的和平政策。

 

Tyrosine   英 /'taɪrəsiːn/   美 /'taɪrəsɪn/

释    义   n. [生化] 酪氨酸

例    句   Experts can not eat anything for depression, the problem was first set out the tyrosine content of foods and beverages, such as Chen cheese, canned meat, soy sauce, yeast extract, herring and salmon. 专家对于抑郁症不能吃什么这一问题首先罗列出了酪氨酸含量高的食物和饮料,如陈乳酪,罐头肉,酱油,酵母提取物,鲱鱼和鲑鱼等。

 

Kinase   英 /ˈkaɪneɪz/   美 /ˈkɪnneɪz/

释    义   n. [生化] 激酶;致活酶

例    句   However, the involvement of tyrosine kinase either directly or through the prostaglandins and nitric oxide synthase in response to inflammation during diabetes is not completely understood.不过,酪氨酸激酶是直接参与还是通过前列腺素和一氧化氮合酶对糖尿病炎症产生反应的,我们目前还不清楚。

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