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 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.

MicroRNA-363-3p/sphingosine-1-phosphate receptor 1 axis inhibits sepsis-induced acute lung injury via the inactivation of nuclear factor kappa-B ligand signaling

“…A previous study suggested that macrophage S1PR1 deletion enhanced angiogenesis and inflammation in a mouse model of imiquimod-induced psoriasis [ 15 ]. Another study revealed that platelet aggregation is enhanced by S1PR1 activation [ 37 ]. In this study, upregulation of macrophage S1PR1 expression was found in lung tissues of septic mice after miR-363-3p knockdown.…”

Sphingolipid Metabolism and Signaling in Lung Cancer: A Potential Therapeutic Target

“…Active sphingolipid metabolism with significantly elevated levels of metabolites, including sphingomyelin (SM) and ceramide, was found in H 2 O 2 -stimulated human platelets [ 41 ]. Liu et al demonstrated that exogenous S1P can alter platelet function in a concentration-dependent manner, with low concentrations of S1P initiating platelet function and high concentrations inhibiting platelet responses [ 42 ]. Ceramidase inhibition significantly blunted glycoprotein VI (GPVI)-induced platelet aggregation, which could be partially overcome by exogenous sphingosine [ 43 ].…”

Structural basis for receptor selectivity and inverse agonism in S1P5 receptors

“…and immune (NK cells) systems 8 . S1P 5 also inhibits PAR-1 mediated platelet activation 9 . This receptor plays an important role in autoimmune 10 and neurodegenerative disorders 10,11 as well as carcinogenesis 12 .…”

“…S1P receptors have different expression profiles -S1P1-S1P3 are expressed in all organs throughout the body, while S1P4 expression is limited to the immune system, and S1P5 is predominantly expressed in the nervous (oligodendrocytes) and immune (NK cells) systems 8 . S1P5 also inhibits PAR-1 mediated platelet activation 9 . This receptor plays an important role in autoimmune 10 and neurodegenerative disorders 10,11 as well as carcinogenesis 12 .…”