Ceramidase critically affects GPVI-dependent platelet activation and thrombus formation.

Abstract

Platelet aggregation, dense granule secretion and thrombus formation are dependent on sphingolipids like ceramide and sphingosine as well as sphingosine-1 phosphate. Sphingosine/ceramide metabolism involves ceramide synthases and ceramidases. However, the role of ceramide synthase and ceramidase in the regulation of platelet function remained ill-defined. The present study determined transmission light aggregometry, employed luciferase based ATP release measurements and studied in vitro thrombus formation under high arterial shear rates in order to define the impact of pharmacological inhibition of serine palmitoyltransferase, ceramide synthase and ceramidase on platelet function. As a result, inhibition of ceramidase significantly blunted collagen related peptide (CRP) induced glyocoprotein VI (GPVI)-dependent platelet aggregation, ATP release and thrombus formation on a collagen-coated surface under shear rates of 1700-sec. Defective platelet aggregation after ceramidase inhibition could partially be overcome by exogenous sphingosine treatment reflecting a pivotal role of ceramidase-derived sphingosine in platelet function. Inhibition of serine palmitoyltransferase and ceramide synthase did not significantly modify GPVI-dependent platelet activation. In conclusion, the present study unraveled ceramidase as a crucial player in sphingosine-induced platelet activation following GPVI-dependent signaling.

• Authors: Patrick Münzer, Sophie Mittelstädt, Sascha Geue, Mailin-Christin Manke, Britta Walker-Allgaier, Florian Lang, Meinrad Gawaz, Oliver Borst
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 496 Issue 3 Pg. 792-798 (02 12 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 29395079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Platelet Membrane Glycoproteins
• platelet membrane glycoprotein VI
• Ceramidases

Topics

• Animals
• Blood Platelets (enzymology)
• Cells, Cultured
• Ceramidases (metabolism)
• Female
• Male
• Mice
• Platelet Aggregation
• Platelet Membrane Glycoproteins (metabolism)
• Thrombosis (enzymology, metabolism)