Ceramidase critically affects GPVI-dependent platelet activation and thrombus formation

Journal Article · Thu Feb 15 04:00:00 EST 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.01.155· OSTI ID:23127381

Münzer, Patrick; Mittelstädt, Sophie; Geue, Sascha; Manke, Mailin-Christin; Walker-Allgaier, Britta ^[1]; Lang, Florian ^[1]; Gawaz, Meinrad; Borst, Oliver ^[1]

---

1. Department of Cardiology and Cardiovascular Medicine, University of Tübingen (Germany)

Highlights: • Neither ceramide synthase nor serine palmitoyltransferase inhibition modifies GPVI-dependent platelet function. • Ceramidase inhibition impairs platelet aggregation, dense granule secretion and in vitro thrombus formation. • Impaired platelet function during ceramidase inhibition could be overcome by exogenous d-sphingosine. 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{sup −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.

• OSTI ID: 23127381
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 3 Vol. 496; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATP
COLLAGEN
LUCIFERASE
METABOLISM
PEPTIDES
PHOSPHATES
SERINE