Kageyama Yasunari, Doi Tomoaki, Matsushima-Nishiwaki Rie, Iida Yuko, Akamatsu Shigeru, Kondo Akira, Kuroyanagi Gen, Yamamoto Naohiro, Mizutani Jun, Otsuka Takanobu, Tokuda Haruhiko, Iida Hiroki, Kozawa Osamu, Ogura Shinji
Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan.
Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu 501‑1194, Japan.
Mol Med Rep. 2014 Jul;10(1):107-12. doi: 10.3892/mmr.2014.2143. Epub 2014 Apr 15.
We have previously shown that glycoprotein Ib/IX/V activation stimulates the release of the soluble CD40 ligand (sCD40L) via the generation of thromboxane A2 from human platelets. In the present study, the role of Rac, which is a member of the Rho family, was investigated in the thromboxane A2‑stimulated release of platelet‑derived growth factor (PDGF)‑AB and sCD40L in human platelets. U46619, a thromboxane receptor agonist, stimulated the activation of Rac time‑dependently in human platelets, and NSC23766, a selective inhibitor of the Rac‑guanine nucleotide exchange factor interaction, reduced the U46619‑induced platelet aggregation. NSC23766 markedly suppressed the U46619‑induced p38 mitogen-activated protein (MAP) kinase phosphorylation. The thromboxane A2‑induced release of PDGF‑AB and sCD40L was significantly suppressed by NSC23766 in a dose‑dependent manner. In addition, NSC23766 reduced the sCD40L release stimulated by ristocetin, a glycoprotein Ib/IX/V activator. These results indicate that Rac regulates the thromboxane A2‑induced stimulation of PDGF‑AB secretion and sCD40L release via the p38 MAP kinase in human platelets.
我们之前已经表明，糖蛋白Ib/IX/V激活通过从人血小板生成血栓素A2来刺激可溶性CD40配体（sCD40L）的释放。在本研究中，我们研究了Rho家族成员Rac在血栓素A2刺激的人血小板中血小板衍生生长因子（PDGF）-AB和sCD40L释放中的作用。血栓素受体激动剂U46619在人血小板中随时间依赖性地刺激Rac的激活，而Rac-鸟嘌呤核苷酸交换因子相互作用的选择性抑制剂NSC23766减少了U46619诱导的血小板聚集。NSC23766显著抑制了U46619诱导的p38丝裂原活化蛋白（MAP）激酶磷酸化。NSC23766以剂量依赖性方式显著抑制了血栓素A2诱导的PDGF-AB和sCD40L的释放。此外，NSC23766减少了由糖蛋白Ib/IX/V激活剂瑞斯托霉素刺激的sCD40L释放。这些结果表明，Rac通过人血小板中的p38 MAP激酶调节血栓素A2诱导的PDGF-AB分泌和sCD40L释放的刺激。
