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Sphingosine 1-phosphate (S1P) Suppresses the Collagen-Induced Activation of Human Platelets via S1P4 Receptor

Sphingosine 1-phosphate (S1P) Suppresses the Collagen-Induced Activation of Human Platelets via S1P4 Receptor

Takashi Onuma, Kumiko Tanabe, Yuko Kito, Masanori Tsujimoto, Kodai Uematsu, Yukiko Enomoto, Rie Matsushima-Nishiwaki, Tomoaki Doi, Kiyoshi Nagase, Shigeru Akamatsu, Haruhiko Tokuda, Shinji Ogura, Toru Iwama, etc.

Thromb Res. 2017 Aug;156:91-100.

PMID: 28609704

Abstract:

Sphingosine 1-phosphate (S1P) is as an extracellular factor that acts as a potent lipid mediator by binding to specific receptors, S1P receptors (S1PRs). However, the precise role of S1P in human platelets that express S1PRs has not yet been fully clarified. We previously reported that heat shock protein 27 (HSP27) is released from human platelets accompanied by its phosphorylation stimulated by collagen. In the present study, we investigated the effect of S1P on the collagen-induced platelet activation. S1P pretreatment markedly attenuated the collagen-induced aggregation. Co-stimulation with S1P and collagen suppressed collagen-induced platelet activation, but the effect was weaker than that of S1P-pretreatment. The collagen-stimulated secretion of platelet-derived growth factor (PDGF)-AB and the soluble CD40 ligand (sCD40L) release were significantly reduced by S1P. In addition, S1P suppressed the collagen-induced release of HSP27 as well as the phosphorylation of HSP27. S1P significantly suppressed the collagen-induced phosphorylation of p38 mitogen-activated protein kinase. S1P increased the levels of GTP-bound Gαi and GTP-bound Gα13 coupled to S1PPR1 and/or S1PR4. CYM50260, a selective S1PR4 agonist, but not SEW2871, a selective S1PR1 agonist, suppressed the collagen-stimulated platelet aggregation, PDGF-AB secretion and sCD40L release. In addition, CYM50260 reduced the release of phosphorylated-HSP27 by collagen as well as the phosphorylation of HSP27. The selective S1PR4 antagonist CYM50358, which failed to affect collagen-induced HSP27 phosphorylation, reversed the S1P-induced attenuation of HSP27 phosphorylation by collagen. These results strongly suggest that S1P inhibits the collagen-induced human platelet activation through S1PR4 but not S1PR1.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1314212399	CYM50358		1314212-39-9	Price
IAR42414760	S1P4 Receptor Antagonist, CYM50358			Price

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