Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac

Yukiko Enomoto*, Takashi Onuma, Takamitsu Hori, Kumiko Tanabe, Kyohei Ueda, Daisuke Mizutani, Tomoaki Doi, Rie Matsushima-Nishiwaki, Shinji Ogura, Hiroki Iida, Toru Iwama, Osamu Kozawa, Haruhiko Tokuda

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

抄録

CXCL12, belonging to the CXC chemokine family, is a weak agonist of platelet aggregation. We previously reported that the combination of CXCL12 and collagen at low doses synergistically activates platelets via not CXCR7 but CXCR4, a specific receptor for CXCL12 on the plasma membrane. Recently, we reported that not Rho/Rho kinase, but Rac is involved in the platelet aggregation induced by this combination. Ristocetin is an activator of the von Willebrand factor that interacts with glycoprotein (GP) Ib/IX/V, which generates thromboxane A2 via phospholipase A2 activation, resulting in the release of the soluble CD40 ligand (sCD40L) from human platelets. In the present study, we investigated the effects of a combination of ristocetin and CXCL12 at low doses on human platelet activation and its underlying mechanisms. Simultaneous stimulation with ristocetin and CXCL12 at subthreshold doses synergistically induce platelet aggregation. A monoclonal antibody against not CXCR7 but CXCR4 suppressed platelet aggregation induced by the combination of ristocetin and CXCL12 at low doses. This combination induces a transient increase in the levels of both GTP-binding Rho and Rac, followed by an increase in phosphorylated cofilin. The ristocetin and CXCL12-induced platelet aggregation as well as the sCD40L release were remarkably enhanced by Y27362, an inhibitor of Rho-kinase, but reduced by NSC23766, an inhibitor of the Rac-guanine nucleotide exchange factor interaction. These results strongly suggest that the combination of ristocetin and CXCL12 at low doses synergistically induces human platelet activation via Rac and that this activation is negatively regulated by the simultaneous activation of Rho/Rho-kinase.

本文言語英語
論文番号9716
ジャーナルInternational Journal of Molecular Sciences
24
11
DOI
出版ステータス出版済み - 2023/06

ASJC Scopus 主題領域

  • 触媒
  • 分子生物学
  • 分光学
  • コンピュータ サイエンスの応用
  • 物理化学および理論化学
  • 有機化学
  • 無機化学

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