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Sphingosine 1-phosphate produced by sphingosine kinase 2 intrinsically controls platelet aggregation in vitro and in vivo

Urtz, Nicole and Gaertner, Florian and von Bruehl, Marie-Luise and Chandraratne, Sue and Rahimi, Faridun and Zhang, Lin and Barocke, Verena and Beil, Johannes and Schubert, Irene and Lorenz, Michael and Legate, Kyle R. and Beerli, Christian and Ledieu, David and Persohn, Elke and Billich, Andreas and Baumruker, Thomas and Mederos y Schnitzler, Michael and Massberg, Steffen (2015) Sphingosine 1-phosphate produced by sphingosine kinase 2 intrinsically controls platelet aggregation in vitro and in vivo. Circulation Research, 117 (4). pp. 376-387. ISSN -

Abstract

Rationale:
Platelets are known to play a crucial role in hemostasis. Sphingosine kinases 1 and 2 (Sphk) catalyze the conversion of sphingosine (Sph) to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P upon activation, little is known about a potential intrinsic effect of S1P on platelet function.
Objective:
To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function.
Methods and Results:
We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2-/- mutants compared to Sphk1-/- or wildtype (WT) mice, as analyzed by mass spectrometry. Sphk2-/- platelets also failed to secrete S1P upon stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease-activated receptor 4-peptide (PAR4-P) and adenosine-diphosphate (ADP) stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 (S1PR1) through modulation of PAR4-P and ADP induced platelet activation. Finally, we show by intravital microscopy that defective platelet aggregation in Sphk2 deficient mice translates into reduced arterial thrombus stability in vivo.
Conclusions:
We demonstrate that Sphk2 is the major Sphk isoform responsible for the generation of S1P in platelets and plays a pivotal intrinsic role in the control of platelet activation. Correspondingly, Sphk2-deficient mice are protected from arterial thrombosis after vascular injury, but have normal bleeding times. Targeting this pathway could therefore present a new therapeutic strategy to prevent thrombosis.

Item Type: Article
Keywords: sphingosine kinase, sphingosine 1-phosphate, platelet aggregation, arterial thrombosis
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/26075

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