title: Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation.
abstract: Sphingosine 1-phosphate (S1P) is a powerful regulator of platelet formation. Enzymes generating S1P include sphingosine kinase 1. The present study thus explored the role of sphingosine kinase 1 in platelet formation and function. Activation-dependent platelet integrin αIIbβ3 activation and secretion of platelets lacking functional sphingosine kinase 1 (sphk1(-/-)) and of wild-type platelets (sphk1(+/+)) were determined utilizing flow cytometry and chronolume luciferin assay. Cytosolic Ca(2+) activity ([Ca(2+)]i) and aggregation were measured using fura-2 fluorescence and aggregometry, respectively. In vitro platelet adhesion and thrombus formation were evaluated using a flow chamber with shear rates of 1,700 s(-1). Activation-dependent increase of [Ca(2+)]i, degranulation (release of alpha and dense granules), integrin αIIbβ3 activation, and aggregation were all significantly increased in sphk1(-/-) platelets compared with sphk1(+/+) platelets. Moreover, while platelet adhesion and thrombus formation under arterial shear rates were significantly augmented in Sphk1-deficient platelets, bleeding time and blood count were unaffected in sphk1(-/-) mice. In conclusion, sphingosine kinase 1 is a powerful negative regulator of platelet function counteracting degranulation, aggregation, and thrombus formation.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Münzer
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Evi
authors.initials: E
authors.lastname: Schmid
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Walker
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Fotinos
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Madhumita
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Dominik
authors.initials: D
authors.lastname: Rath
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vogel
authors.affiliation: Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.
authors.forename: Sascha M
authors.initials: SM
authors.lastname: Hoffmann
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Katja
authors.initials: K
authors.lastname: Metzger
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Seizer
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Tobias
authors.initials: T
authors.lastname: Geisler
authors.affiliation: Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Gawaz
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany. Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany; and.
authors.forename: Oliver
authors.initials: O
authors.lastname: Borst
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany. florian.lang@uni-tuebingen.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D015539:Platelet Activation / Q000502:physiology*; D013927:Thrombosis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase
keywords: [Ca2+]i; platelet activation; sphingosine kinase 1; thrombus formation