• Nicole Urtz, Florian Gaertner, Marie-Luise von Bruehl, Sue Chandraratne, Faridun Rahimi, Lin Zhang, Mathias Orban, Verena Barocke, Johannes Beil, Irene Schubert, Michael Lorenz, Kyle R Legate, Andrea Huwiler, Josef M Pfeilschifter, Christian Beerli, David Ledieu, Elke Persohn, Andreas Billich, Thomas Baumruker, Michael Mederos y Schnitzler, and Steffen Massberg.
• From the Medizinische Klinik und Poliklinik I, Klinikum der Universität München (N.U., F.G., M.-L.v.B., S.C., F.R., M.O., V.B., J.B., I.S., M.L., K.R.L., S.M.), Department of Applied Physics, Center for NanoSciences (K.R.L.), and Walther-Straub-Institute of Pharmacology and Toxicology (M.M.y.S.), Ludwig-Maximilians-Universität, Munich, Germany; DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (N.U., F.G., M.-L.v.B., S.C., F.R., M.O., J.B., I.S., M.L., M.M.y.S., S.M.); Heart Failure Institute, Research Center for Translational Medicine and Department of Cardiovascular Medicine, East Hospital, Tongji University School of Medicine, Shanghai, China (L.Z.); Institute of Pharmacology, University of Bern, Bern, Switzerland (A.H.); Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany (J.M.P.); and Preclinical Safety (D.L., E.P.), and Autoimmunity, Transplantation and Inflammation (C.B., A.B., T.B.), Novartis Institutes for BioMedical Research, Basel, Switzerland.
• Circ. Res. 2015 Jul 31; 117 (4): 376-87.

RationalePlatelets 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.ObjectiveTo investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function.Methods And ResultsWe 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.ConclusionsWe 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.© 2015 American Heart Association, Inc.

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