Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions
Antithrombotic effects of PAR1 and PAR4 antagonists evaluated under flow and static conditions
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DOI：
10.1016/j.thromres.2013.10.037
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发表时间：
2014-01-01
影响因子：
7.5
通讯作者：
Maruyama, Ikuro
中科院分区：
文献类型：
--
作者：
Hosokawa, Kazuya;Ohnishi, Tomoko;Maruyama, Ikuro
引言：凝血酶介导的人血小板活化涉及G蛋白偶联的蛋白酶活化受体PAR1和PAR4。抑制PAR1和/或PAR4被认为可调节血小板活化及随后的促凝血反应。然而，PAR1和PAR4拮抗作用的抗血栓效应尚未完全阐明，特别是在血流条件下。
材料与方法：采用基于微芯片的流室系统，在模拟中小动脉（600 s⁻¹）以及大动脉和小静脉（240 s⁻¹）所经历的剪切速率下，评估SCH79797（PAR1拮抗剂）和YD - 3（PAR4拮抗剂）对胶原蛋白和组织凝血活酶介导的血栓形成的影响。
结果：在剪切速率为600 s⁻¹时，SCH79797（10 μM）有效减少了富含纤维蛋白的血小板血栓，并显著延迟了流室毛细血管的堵塞（是对照组的1.44倍；P < 0.001）。SCH79797的抑制活性在240 s⁻¹时减弱。YD - 3（20 μM）在两种剪切速率下均无显著作用。当与阿司匹林和AR - C66096（P2Y₁₂拮抗剂）联合使用时，SCH79797的抗血栓效应显著增强，但与YD - 3联合使用时则无此效果。相反，在静态条件下，用SCH79797和YD - 3处理的血液中未观察到对组织因子诱导的凝血块形成有显著抑制作用，尽管这些拮抗剂对富血小板血浆中的凝血酶生成有轻微延迟。
结论：我们的研究结果表明，PAR1和/或PAR4拮抗作用的抗血栓活性受剪切条件以及与阿司匹林和P2Y₁₂拮抗剂联合抑制血小板的影响。（C）2013爱思唯尔有限公司。保留所有权利。
Introduction: Thrombin-mediated activation of human platelets involves the G-protein-coupled protease-activated receptors PAR1 and PAR4. Inhibition of PAR1 and/or PAR4 is thought to modulate platelet activation and subsequent procoagulant reactions. However, the antithrombotic effects of PAR1 and PAR4 antagonism have not been fully elucidated, particularly under flow conditions.Materials and Methods: A microchip-based flow chamber system was used to evaluate the influence of SCH79797 (PAR1 antagonist) and YD-3 (PAR4 antagonist) on thrombus formation mediated by collagen and tissue thromboplastin at shear rates simulating those experienced in small- to medium-sized arteries (600 s(-1)) and large arteries and small veins (240 s(-1)).Results: At a shear rate of 600 s(-1), SCH79797 (10 mu M) efficiently reduced fibrin-rich platelet thrombi and significantly delayed occlusion of the flow chamber capillary (1.44 fold of control; P < 0.001). The inhibitory activity of SCH79797 was diminished at 240 s(-1). YD-3 (20 mu M) had no significant effect at either shear rate. The antithrombotic effects of SCH79797 were significantly augmented when combined with aspirin and AR-C66096 (P2Y(12) antagonist), but not with YD-3. In contrast, no significant inhibition of tissue factor-induced clot formation under static conditions was observed in blood treated with SCH79797 and YD-3, although thrombin generation in platelet-rich plasma was weakly delayed by these antagonists.Conclusions: Our results suggest that the antithrombotic activities of PAR1 and/or PAR4 antagonism is influenced by shear conditions as well as by combined platelet inhibition with aspirin and a P2Y(12)-antagonist. (C) 2013 Elsevier Ltd. All rights reserved.