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Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac
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 r...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253402/ https://www.ncbi.nlm.nih.gov/pubmed/37298667 http://dx.doi.org/10.3390/ijms24119716 |
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author | Enomoto, Yukiko Onuma, Takashi Hori, Takamitsu Tanabe, Kumiko Ueda, Kyohei Mizutani, Daisuke Doi, Tomoaki Matsushima-Nishiwaki, Rie Ogura, Shinji Iida, Hiroki Iwama, Toru Kozawa, Osamu Tokuda, Haruhiko |
author_facet | Enomoto, Yukiko Onuma, Takashi Hori, Takamitsu Tanabe, Kumiko Ueda, Kyohei Mizutani, Daisuke Doi, Tomoaki Matsushima-Nishiwaki, Rie Ogura, Shinji Iida, Hiroki Iwama, Toru Kozawa, Osamu Tokuda, Haruhiko |
author_sort | Enomoto, Yukiko |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10253402 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102534022023-06-10 Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac Enomoto, Yukiko Onuma, Takashi Hori, Takamitsu Tanabe, Kumiko Ueda, Kyohei Mizutani, Daisuke Doi, Tomoaki Matsushima-Nishiwaki, Rie Ogura, Shinji Iida, Hiroki Iwama, Toru Kozawa, Osamu Tokuda, Haruhiko Int J Mol Sci Article 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. MDPI 2023-06-03 /pmc/articles/PMC10253402/ /pubmed/37298667 http://dx.doi.org/10.3390/ijms24119716 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Enomoto, Yukiko Onuma, Takashi Hori, Takamitsu Tanabe, Kumiko Ueda, Kyohei Mizutani, Daisuke Doi, Tomoaki Matsushima-Nishiwaki, Rie Ogura, Shinji Iida, Hiroki Iwama, Toru Kozawa, Osamu Tokuda, Haruhiko Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac |
title | Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac |
title_full | Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac |
title_fullStr | Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac |
title_full_unstemmed | Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac |
title_short | Synergy by Ristocetin and CXCL12 in Human Platelet Activation: Divergent Regulation by Rho/Rho-Kinase and Rac |
title_sort | synergy by ristocetin and cxcl12 in human platelet activation: divergent regulation by rho/rho-kinase and rac |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10253402/ https://www.ncbi.nlm.nih.gov/pubmed/37298667 http://dx.doi.org/10.3390/ijms24119716 |
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