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

• Published in: Scientific reports Vol. 11; no. 1; pp. 15308 - 14
• Main Authors: Liu, Haonan, Jackson, Molly L., Goudswaard, Lucy J., Moore, Samantha F., Hutchinson, James L., Hers, Ingeborg
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/436; 631/80; Agonists; Antagonists; Blood Platelets - drug effects; Blood Platelets - ultrastructure; Carrier Proteins - pharmacology; Cell Shape - drug effects; Diabetes mellitus; Dose-Response Relationship, Drug; Humanities and Social Sciences; Humans; Kinases; Lysophospholipids - agonists; Lysophospholipids - antagonists & inhibitors; Lysophospholipids - pharmacology; multidisciplinary; Peptide Fragments - pharmacology; Peptides - pharmacology; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - physiology; Platelet Activation - drug effects; Platelet aggregation; Platelet Aggregation - drug effects; Proteinase-activated receptor 1; Receptor mechanisms; Receptor, PAR-1 - agonists; Science; Science (multidisciplinary); Sphingosine - agonists; Sphingosine - analogs & derivatives; Sphingosine - antagonists & inhibitors; Sphingosine - pharmacology; Sphingosine 1-phosphate; Sphingosine kinase; Sphingosine-1-Phosphate Receptors - drug effects; Sphingosine-1-Phosphate Receptors - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-94052-4

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 S1PR 1 receptor activation has a positive priming effect, S1PR 2 and S1PR 3 have no effect on platelet function, whereas S1PR 4 and S1PR 5 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.