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首页> 外文期刊>Journal of thrombosis and haemostasis: JTH >Small molecule targeting the Rac1‐ NOX NOX 2 interaction prevents collagen‐related peptide and thrombin‐induced reactive oxygen species generation and platelet activation
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Small molecule targeting the Rac1‐ NOX NOX 2 interaction prevents collagen‐related peptide and thrombin‐induced reactive oxygen species generation and platelet activation

机译：靶向RAC1- NOx NOx 2相互作用的小分子可防止胶原相关的肽和凝血酶诱导的反应性氧物种产生和血小板活化

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Essentials Reactive oxygen species (ROS) generation by NOX2 plays a critical role in platelet activation. Rac1 regulation of NOX2 is important for ROS generation. Small molecule inhibitor of the Rac1‐p67 phox interaction prevents platelet activation. Pharmacologic targeting of Rac1‐NOX2 axis can be a viable approach for antithrombotic therapy. Summary Background Platelets from patients with X‐linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX 2 exhibit diminished reactive oxygen species ( ROS ) generation and platelet activation. Binding of Rac1 GTP ase to p67 phox plays a critical role in NOX 2 activation by facilitating the assembly of the NOX 2 enzyme complex. Objective We tested the hypothesis that Phox‐I, a rationally designed small molecule inhibitor of Rac–p67 phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Results Collagen‐related peptide ( CRP ) induced ROS generation in a time‐dependent manner. Platelets from Rac1 ?/? mice or human platelets treated with NSC 23766, a specific Rac inhibitor, produced significantly less ROS in response to CRP . Treatment of platelets with Phox‐I inhibited diverse CRP ‐induced responses, including: (i) ROS generation; (ii) release of P‐selectin; (iii) secretion of ATP ; (iv) platelet aggregation; and (v) phosphorylation of Akt. Similarly, incubation of platelets with Phox‐I inhibited thrombin‐induced: (i) secretion of ATP ; (ii) platelet aggregation; (iii) rise in cytosolic calcium; and (iv) phosphorylation of Akt. In mouse models, intraperitoneal administration of Phox‐I inhibited: (i) collagen‐induced platelet aggregation without affecting the tail bleeding time and (ii) in?vivo platelet adhesion/accumulation at the laser injury sites on the saphenous vein without affecting the time for complete cessation of blood loss. Conclusions Small molecule targeting of the Rac1–p67 phox interaction may present an antithrombosis regimen by preventing GPVI ‐ and non‐ GPVI ‐mediated NOX 2 activation, ROS generation and platelet function without affecting the bleeding time.
机译：NOx2的Essentials反应性氧（ROS）产生在血小板激活中起着关键作用。 RAC1 NOX2的调节对于ROS生成很重要。 RAC1-P67 PHOX相互作用的小分子抑制剂可防止血小板活化。 Rac1-Nox2轴的药理靶向可以是抗血栓形成治疗的可行方法。发明内容X型慢性肉芽肿疾病或小鼠缺乏烟氨基酰胺腺嘌呤二核苷酸（磷酸）（NAD（P）H）氧化酶同种型NOx 2的血小板血小板表现出反应性氧物质（ROS）产生和血小板活化。 RAC1 GTP ASE与P67 PHOX的结合通过促进NOx 2酶络合物的组装，在NOx 2激活中起着关键作用。目的我们测试了Phox-i，理性设计的Rac-p67 Phox相互作用的合理设计的小分子抑制剂，可以通过抑制ROS产生和血小板活化作为抗粘结剂。结果胶原蛋白相关的肽（CRP）以时间依赖的方式诱导ROS产生。 RAC1的血小板？/？用NSC 23766处理的小鼠或人血小板，特定的RAC抑制剂，响应于CRP而显着较低的RO。用Phox-i血小板治疗血小板抑制不同的CRP诱导的反应，包括：（i）ros生成; （ii）p-selectin的释放; （iii）ATP的分泌; （iv）血小板聚集; （v）akt的磷酸化。类似地，用Phox-i抑制血小板诱导的血小板诱导的血小板：（i）分泌ATP; （ii）血小板汇总; （iii）胞质钙升高; （iv）akt的磷酸化。在小鼠模型中，腹腔内施用Phox-i抑制：（i）胶原诱导的血小板聚集，而不影响尾部出血时间和（ii）在α体内血小板粘附/积聚在静脉静脉上的粘附/积累而不影响时间的情况下完全停止失血。结论RAC1-P67 PHOX相互作用的小分子靶向可以通过预防GPVI和非GPVI介导的NOx 2激活，ROS生成和血小板函数来呈现抗血栓形成方案，而不会影响出血时间。

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