Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo. Issue 4 (31st July 2015)

• Record Type: Journal Article
• Authors: Urtz, Nicole; Gaertner, Florian; von Bruehl, Marie-Luise; Chandraratne, Sue; Rahimi, Faridun; Zhang, Lin; 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; Schnitzler, Michael Mederos y; Massberg, Steffen
• Is Part Of: Circulation research. Volume 117:Issue 4(2015)
• Publication Date: 2015-07-31
• Subjects: Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.115.306901
• Languages: English
• ISSNs: 0009-7330

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title> <underline>Rationale:</underline> </title> <p>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.</p> </sec> <sec> <title> <underline>Objective:</underline> </title> <p>To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function.</p> </sec> <sec> <title> <underline>Methods and Results:</underline> </title> <p>We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2<sup>−/−</sup> mutants compared with Sphk1<sup>−/−</sup> or wild-type mice, as analyzed by mass spectrometry. Sphk2<sup>−/−</sup> 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.</p> </sec> <sec> <title> <underline>Conclusions:</underline> </title> <p>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.</p> </sec> </abstract>