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Title

Time-dependent inhibitory effects of cGMP-analogues on thrombin-induced platelet-derived microparticles formation, platelet aggregation, and P-selectin expression

AuthorsNygaard, Gyrid; Herfindal, Lars; Kopperud, Reidun; Aragay, Anna M. ; Holmsen, Holm; Doskeland, Stein Ove; Kleppe, Rune; Selheim, Frode
AdvisorVASP
KeywordscAMP
cGMP
cGMP-analogues
PKG
Platelets
Issue Date4-Jul-2014
PublisherAcademic Press
CitationBiochemical and Biophysical Research Communications 449(3): 357-363 (2014)
AbstractIn platelets, nitric oxide (NO) activates cGMP/PKG signalling, whereas prostaglandins and adenosine signal through cAMP/PKA. Cyclic nucleotide signalling has been considered to play an inhibitory role in platelets. However, an early stimulatory effect of NO and cGMP-PKG signalling in low dose agonist-induced platelet activation have recently been suggested. Here, we investigated whether different experimental conditions could explain some of the discrepancy reported for platelet cGMP-PKG-signalling. We treated gel-filtered human platelets with cGMP and cAMP analogues, and used flow cytometric assays to detect low dose thrombin-induced formation of small platelet aggregates, single platelet disappearance (SPD), platelet-derived microparticles (PMP) and thrombin receptor agonist peptide (TRAP)-induced P-selectin expression. All four agonist-induced platelet activation phases were blocked when platelets were costimulated with the PKG activators 8-Br-PET-cGMP or 8-pCPT-cGMP and low-doses of thrombin or TRAP. However, extended incubation with 8-Br-PET-cGMP decreased its inhibition of TRAP-induced P-selectin expression in a time-dependent manner. This effect did not involve desensitisation of PKG or PKA activity, measured as site-specific VASP phosphorylation. Moreover, PKG activators in combination with the PKA activator Sp-5,6-DCL-cBIMPS revealed additive inhibitory effect on TRAP-induced P-selectin expression. Taken together, we found no evidence for a stimulatory role of cGMP/PKG in platelets activation and conclude rather that cGMP/PKG signalling has an important inhibitory function in human platelet activation. © 2014 Elsevier Inc. All rights reserved.
Publisher version (URL)http://dx.doi.org/10.1016/j.bbrc.2014.05.032
URIhttp://hdl.handle.net/10261/124438
DOI10.1016/j.bbrc.2014.05.032
Identifiersdoi: 10.1016/j.bbrc.2014.05.032
issn: 1090-2104
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