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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Center of Regenerative Medicine for Skeletal Tissues [discontinued]
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Center of Regenerative Medicine for Skeletal Tissues [discontinued]

UniBE Contributor:

Zhang, Lingli and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0009-7330

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Debora Scherrer

Date Deposited:

23 Feb 2016 09:04

Last Modified:

23 Feb 2016 09:04

Publisher DOI:

10.1161/CIRCRESAHA.115.306901

PubMed ID:

26129975

Uncontrolled Keywords:

blood platelets; platelet aggregation; sphingosine 1-phosphate; sphingosine kinase; thrombosis

BORIS DOI:

10.7892/boris.76762

URI:

https://boris.unibe.ch/id/eprint/76762

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