Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo

Urtz, Nicole; Gaertner, Florian; von Bruehl, Marie-Luise; Chandraratne, Sue; Rahimi, Faridun; Zhang, Lingli; Orban, Mathias; Barocke, Verena; Beil, Johannes; Schubert, Irene; Lorenz, Michael; Legate, Kyle R; Huwiler, Andrea; Pfeilschifter, Josef M; Beerli, Christian; Ledieu, David; Persohn, Elke; Billich, Andreas; Baumruker, Thomas; Mederos y Schnitzler, Michael; ... (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. Lippincott Williams & Wilkins 10.1161/CIRCRESAHA.115.306901

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RATIONALE

Platelets are known to play a crucial role in hemostasis. Sphingosine kinases (Sphk) 1 and 2 catalyze the conversion of sphingosine to the bioactive metabolite sphingosine 1-phosphate (S1P). Although platelets are able to secrete S1P on 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 with Sphk1(-/-) or wild-type mice, as analyzed by mass spectrometry. Sphk2(-/-) platelets also failed to secrete S1P on stimulation. Blood from Sphk2-deficient mice showed decreased aggregation after protease-activated receptor 4-peptide and adenosine diphosphate stimulation in vitro, as assessed by whole blood impedance aggregometry. We revealed that S1P controls platelet aggregation via the sphingosine 1-phosphate receptor 1 through modulation of protease-activated receptor 4-peptide and adenosine diphosphate-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.

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5 Citations in Web of Science ®
6 Citations in Scopus

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