Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner

Abstract Sphingosine 1-phosphate (S1P) is a bioactive signalling sphingolipid that is increased in diseases such as obesity and diabetes. S1P can modulate platelet function, however the direction of effect and S1P receptors (S1PRs) involved are controversial. Here we describe the role of S1P in regu...

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Autores principales:	Haonan Liu, Molly L. Jackson, Lucy J. Goudswaard, Samantha F. Moore, James L. Hutchinson, Ingeborg Hers
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/54f3d48ee6ef49698d91107aee9c25b1
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spelling	oai:doaj.org-article:54f3d48ee6ef49698d91107aee9c25b12021-12-02T16:24:52ZSphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner10.1038/s41598-021-94052-42045-2322https://doaj.org/article/54f3d48ee6ef49698d91107aee9c25b12021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94052-4https://doaj.org/toc/2045-2322Abstract Sphingosine 1-phosphate (S1P) is a bioactive signalling sphingolipid that is increased in diseases such as obesity and diabetes. S1P can modulate platelet function, however the direction of effect and S1P receptors (S1PRs) involved are controversial. Here we describe the role of S1P in regulating human platelet function and identify the receptor subtypes responsible for S1P priming. Human platelets were treated with protease-activated receptor 1 (PAR-1)-activating peptide in the presence or absence of S1P, S1PR agonists or antagonists, and sphingosine kinases inhibitors. S1P alone did not induce platelet aggregation but at low concentrations S1P enhanced PAR1-mediated platelet responses, whereas PAR1 responses were inhibited by high concentrations of S1P. This biphasic effect was mimicked by pan-S1PR agonists. Specific agonists revealed that S1PR1 receptor activation has a positive priming effect, S1PR2 and S1PR3 have no effect on platelet function, whereas S1PR4 and S1PR5 receptor activation have an inhibitory effect on PAR-1 mediated platelet function. Although platelets express both sphingosine kinase 1/2, enzymes which phosphorylate sphingosine to produce S1P, only dual and SphK2 inhibition reduced platelet function. These results support a role for SphK2-mediated S1P generation in concentration-dependent positive and negative priming of platelet function, through S1PR1 and S1PR4/5 receptors, respectively.Haonan LiuMolly L. JacksonLucy J. GoudswaardSamantha F. MooreJames L. HutchinsonIngeborg HersNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Haonan Liu Molly L. Jackson Lucy J. Goudswaard Samantha F. Moore James L. Hutchinson Ingeborg Hers Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner
description	Abstract Sphingosine 1-phosphate (S1P) is a bioactive signalling sphingolipid that is increased in diseases such as obesity and diabetes. S1P can modulate platelet function, however the direction of effect and S1P receptors (S1PRs) involved are controversial. Here we describe the role of S1P in regulating human platelet function and identify the receptor subtypes responsible for S1P priming. Human platelets were treated with protease-activated receptor 1 (PAR-1)-activating peptide in the presence or absence of S1P, S1PR agonists or antagonists, and sphingosine kinases inhibitors. S1P alone did not induce platelet aggregation but at low concentrations S1P enhanced PAR1-mediated platelet responses, whereas PAR1 responses were inhibited by high concentrations of S1P. This biphasic effect was mimicked by pan-S1PR agonists. Specific agonists revealed that S1PR1 receptor activation has a positive priming effect, S1PR2 and S1PR3 have no effect on platelet function, whereas S1PR4 and S1PR5 receptor activation have an inhibitory effect on PAR-1 mediated platelet function. Although platelets express both sphingosine kinase 1/2, enzymes which phosphorylate sphingosine to produce S1P, only dual and SphK2 inhibition reduced platelet function. These results support a role for SphK2-mediated S1P generation in concentration-dependent positive and negative priming of platelet function, through S1PR1 and S1PR4/5 receptors, respectively.
format	article
author	Haonan Liu Molly L. Jackson Lucy J. Goudswaard Samantha F. Moore James L. Hutchinson Ingeborg Hers
author_facet	Haonan Liu Molly L. Jackson Lucy J. Goudswaard Samantha F. Moore James L. Hutchinson Ingeborg Hers
author_sort	Haonan Liu
title	Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner
title_short	Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner
title_full	Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner
title_fullStr	Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner
title_full_unstemmed	Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner
title_sort	sphingosine-1-phosphate modulates par1-mediated human platelet activation in a concentration-dependent biphasic manner
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/54f3d48ee6ef49698d91107aee9c25b1
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Sphingosine-1-phosphate modulates PAR1-mediated human platelet activation in a concentration-dependent biphasic manner

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