Small molecule targeting the Rac1-NOX2 interaction prevents collagen-related peptide and thrombin-induced reactive oxygen species generation and platelet activation.
Small molecule targeting the Rac1-NOX2 interaction prevents collagen-related peptide and thrombin-induced reactive oxygen species generation and platelet activation.
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靶向Rac1-Nox2相互作用的小分子可防止胶原蛋白相关的肽和凝血酶诱导的活性氧的产生和血小板激活。
DOI：
10.1111/jth.14240
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发表时间：
2018-10
期刊：
影响因子：
--
通讯作者：
Zheng Y
中科院分区：
文献类型：
--
作者：
Akbar H;Duan X;Piatt R;Saleem S;Davis AK;Tandon NN;Bergmeier W;Zheng Y
来自X连锁慢性肉芽肿病患者或烟酰胺腺嘌呤二核苷酸（磷酸）（NAD（P）H）氧化酶亚型NOX 2缺陷小鼠的血小板显示活性氧（ROS）生成和血小板活化减少。Rac 1 GT3与p67 phox的结合通过促进NOX 2酶复合物的组装在NOX 2活化中起关键作用。我们测试的假设，Phox-I，一个合理设计的小分子Rac-p67 phox相互作用的抑制剂，可能作为一种抗血栓形成剂，通过抑制ROS的产生和血小板活化。胶原相关肽（CRP）诱导ROS的产生在一个时间依赖性的方式。用NSC 23766（一种特异性Rac抑制剂）处理的Rac 1 −/−小鼠或人血小板的血小板对CRP产生的ROS显著减少。用Phox-I处理血小板抑制多种CRP诱导的应答，包括：（i）ROS产生;（ii）P-选择素的释放;（iii）ATP的分泌;（iv）血小板聚集;和（v）Akt的磷酸化。类似地，血小板与Phox-I的孵育抑制凝血酶诱导的：（i）ATP的分泌;（ii）血小板聚集;（iii）细胞溶质钙的升高;和（iv）Akt的磷酸化。在小鼠模型中，腹腔内给予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;（ii）隐静脉激光损伤部位的体内血小板粘附/积聚，而不影响失血完全停止的时间。靶向Rac 1-p67 phox相互作用的小分子可以通过防止GPVI和非GPVI介导的NOX 2活化、ROS产生和血小板功能而不影响出血时间来提供抗血栓形成方案。
Platelets from patients with X-linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX2 exhibit diminished reactive oxygen species (ROS) generation and platelet activation. Binding of Rac1 GTPase to p67phox plays a critical role in NOX2 activation by facilitating the assembly of the NOX2 enzyme complex. We tested the hypothesis that Phox-I, a rationally designed small molecule inhibitor of Rac–p67phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Collagen-related peptide (CRP) induced ROS generation in a time-dependent manner. Platelets from Rac1−/− mice or human platelets treated with NSC23766, 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. Small molecule targeting of the Rac1–p67phox interaction may present an antithrombosis regimen by preventing GPVI- and non-GPVI-mediated NOX2 activation, ROS generation and platelet function without affecting the bleeding time.
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影响因子：
3.7
作者：
Perveen R;Funk K;Thuma J;Wulf Ridge S;Cao Y;Akkerman JW;Chen X;Akbar H
通讯作者：
Akbar H
DOI：
10.1074/jbc.m116.746867
发表时间：
2017-02-03
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Battram AM;Durrant TN;Agbani EO;Heesom KJ;Paul DS;Piatt R;Poole AW;Cullen PJ;Bergmeier W;Moore SF;Hers I
通讯作者：
Hers I
DOI：
10.1161/atvbaha.116.307308
发表时间：
2016-05
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Delaney MK;Kim K;Estevez B;Xu Z;Stojanovic-Terpo A;Shen B;Ushio-Fukai M;Cho J;Du X
通讯作者：
Du X
影响因子：
56.9
作者：
Gu, Y;Filippi, MD;Williams, DA
通讯作者：
Williams, DA
影响因子：
4.8
作者：
Cheng, Guangjie;Diebold, Becky A.;Lambeth, J. David
通讯作者：
Lambeth, J. David