Pharmacologic targeting of Cdc42 GTPase by a small molecule Cdc42 activity-specific inhibitor prevents platelet activation and thrombosis.
Pharmacologic targeting of Cdc42 GTPase by a small molecule Cdc42 activity-specific inhibitor prevents platelet activation and thrombosis.
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小分子Cdc42活性特异性抑制剂靶向Cdc42 GTPase可防止血小板活化和血栓形成。
DOI：
10.1038/s41598-021-92654-6
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发表时间：
2021-06-23
影响因子：
4.6
通讯作者：
Akbar H
中科院分区：
文献类型：
--
作者：
Duan X;Perveen R;Dandamudi A;Adili R;Johnson J;Funk K;Berryman M;Davis AK;Holinstat M;Zheng Y;Akbar H
已显示Cdc 42 GTd 3的基因靶向抑制血小板活化。在这项研究中，我们研究了一个假设，即抑制Cdc 42活性的卡辛，小分子Cdc 42活性特异性抑制剂，可能下调血小板活化和血栓形成。我们研究了卡辛对体外血小板活化和体内血栓形成的影响。在人血小板中，卡辛而不是其失活类似物Pirl 7阻断胶原诱导的Cdc 42活化并抑制其下游效应物PAK 1/2的磷酸化。此外，添加卡辛洗涤的人血小板抑制血小板在固定化纤维蛋白原上的铺展。用卡辛处理人血小板抑制胶原或凝血酶诱导的：（a）ATP分泌和血小板聚集;和（B）Akt、ERK和p38-MAPK的磷酸化。用Pirl 7（卡辛的无活性类似物）预孵育血小板未能抑制胶原诱导的聚集。在与卡辛孵育后洗涤人血小板消除了其对胶原诱导的聚集的抑制作用。对野生型小鼠腹膜内给予卡辛可抑制胶原诱导的离体聚集，但不影响鼠尾出血时间。在激光诱导小鼠提睾肌小动脉损伤之前，卡辛给药导致与未用卡辛治疗的对照小鼠相比形成更小且不稳定的血栓。这些数据表明，通过特异性和可逆性抑制剂对Cdc 42进行药理学靶向，可能会发现新的抗血栓药物。
Gene targeting of Cdc42 GTPase has been shown to inhibit platelet activation. In this study, we investigated a hypothesis that inhibition of Cdc42 activity by CASIN, a small molecule Cdc42 Activity-Specific INhibitor, may down regulate platelet activation and thrombus formation. We investigated the effects of CASIN on platelet activation in vitro and thrombosis in vivo. In human platelets, CASIN, but not its inactive analog Pirl7, blocked collagen induced activation of Cdc42 and inhibited phosphorylation of its downstream effector, PAK1/2. Moreover, addition of CASIN to washed human platelets inhibited platelet spreading on immobilized fibrinogen. Treatment of human platelets with CASIN inhibited collagen or thrombin induced: (a) ATP secretion and platelet aggregation; and (b) phosphorylation of Akt, ERK and p38-MAPK. Pre-incubation of platelets with Pirl7, an inactive analog of CASIN, failed to inhibit collagen induced aggregation. Washing of human platelets after incubation with CASIN eliminated its inhibitory effect on collagen induced aggregation. Intraperitoneal administration of CASIN to wild type mice inhibited ex vivo aggregation induced by collagen but did not affect the murine tail bleeding times. CASIN administration, prior to laser-induced injury in murine cremaster muscle arterioles, resulted in formation of smaller and unstable thrombi compared to control mice without CASIN treatment. These data suggest that pharmacologic targeting of Cdc42 by specific and reversible inhibitors may lead to the discovery of novel antithrombotic agents.
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DOI：
10.1074/jbc.m112.435941
发表时间：
2013-03-22
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Hong L;Kenney SR;Phillips GK;Simpson D;Schroeder CE;Nöth J;Romero E;Swanson S;Waller A;Strouse JJ;Carter M;Chigaev A;Ursu O;Oprea T;Hjelle B;Golden JE;Aubé J;Hudson LG;Buranda T;Sklar LA;Wandinger-Ness A
通讯作者：
Wandinger-Ness A
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
影响因子：
5.5
作者：
Aslan, Joseph E.;Baker, Sandra M.;McCarty, Owen J. T.
通讯作者：
McCarty, Owen J. T.
影响因子：
23.9
作者：
Florian, Maria Carolina;Doerr, Karin;Niebel, Anja;Daria, Deidre;Schrezenmeier, Hubert;Rojewski, Markus;Filippi, Marie-Dominique;Hasenberg, Anja;Gunzer, Matthias;Scharffetter-Kochanek, Karin;Zheng, Yi;Geiger, Hartmut
通讯作者：
Geiger, Hartmut
影响因子：
14.8
作者：
Henry, EP;Peterson, JR;Kirchhausen, T
通讯作者：
Kirchhausen, T