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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; Mederos y Schnitzler, Michael; Massberg, Steffen

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

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  • Medientyp: E-Artikel
  • Titel: Sphingosine 1-Phosphate Produced by Sphingosine Kinase 2 Intrinsically Controls Platelet Aggregation In Vitro and In Vivo
  • Beteiligte: 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; Mederos y Schnitzler, Michael; Massberg, Steffen
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2015
  • Erschienen in: Circulation Research
  • Sprache: Englisch
  • DOI: 10.1161/circresaha.115.306901
  • ISSN: 0009-7330; 1524-4571
  • Schlagwörter: Cardiology and Cardiovascular Medicine ; Physiology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats: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.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To investigate the role of Sphk1- and Sphk2-derived S1P in the regulation of platelet function.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p> We found a 100-fold reduction in intracellular S1P levels in platelets derived from Sphk2 <jats:sup>−/−</jats:sup> mutants compared with Sphk1 <jats:sup>−/−</jats:sup> or wild-type mice, as analyzed by mass spectrometry. Sphk2 <jats:sup>−/−</jats: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. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats: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.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang