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Farnesyl pyrophosphate is an endogenous antagonist to ADP-stimulated P2Y12 receptor-mediated platelet aggregation.

Högberg, Carl LU ; Gidlöf, Olof LU ; Deflorian, F; Jacobson, K A; Abdelrahman, A; Müller, C E; Olde, Björn LU and Erlinge, David LU (2012) In Thrombosis and Haemostasis 108(1). p.119-132
Abstract
Farnesyl pyrophosphate (FPP) is an intermediate in cholesterol biosynthesis, and it has also been reported to activate platelet LPA (lysophosphatidic acid) receptors. The aim of this study was to investigate the role of extracellular FPP in platelet aggregation. Human platelets were studied with light transmission aggregometry, flow cytometry and [35S]GTPγS binding assays. As shown previously, FPP could potentiate LPA-stimulated shape change. Surprisingly, FPP also acted as a selective insurmountable antagonist to ADP-induced platelet aggregation. FPP inhibited ADP-induced expression of P-selectin and the activated glycoprotein (Gp)IIb/IIIa receptor. FPP blocked ADP-induced inhibition of cAMP accumulation and [35S]GTPγS binding in... (More)
Farnesyl pyrophosphate (FPP) is an intermediate in cholesterol biosynthesis, and it has also been reported to activate platelet LPA (lysophosphatidic acid) receptors. The aim of this study was to investigate the role of extracellular FPP in platelet aggregation. Human platelets were studied with light transmission aggregometry, flow cytometry and [35S]GTPγS binding assays. As shown previously, FPP could potentiate LPA-stimulated shape change. Surprisingly, FPP also acted as a selective insurmountable antagonist to ADP-induced platelet aggregation. FPP inhibited ADP-induced expression of P-selectin and the activated glycoprotein (Gp)IIb/IIIa receptor. FPP blocked ADP-induced inhibition of cAMP accumulation and [35S]GTPγS binding in platelets. In Chinese hamster ovary cells expressing the P2Y12 receptor, FPP caused a rightward shift of the [35S]GTPγS binding curve. In Sf9 insect cells expressing the human P2Y12 receptor, FPP showed a concentration-dependent, although incomplete inhibition of [3H]PSB-0413 binding. Docking of FPP in a P2Y12 receptor model revealed molecular similarities with ADP and a good fit into the binding pocket for ADP. In conclusion, FPP is an insurmountable antagonist of ADP-induced platelet aggregation mediated by the P2Y12 receptor. It could be an endogenous antithrombotic factor modulating the strong platelet aggregatory effects of ADP in a manner similar to the use of clopidogrel, prasugrel or ticagrelor in the treatment of ischaemic heart disease. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Thrombosis and Haemostasis
volume
108
issue
1
pages
119 - 132
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • wos:000306538400017
  • pmid:22628078
  • scopus:84863656524
ISSN
0340-6245
DOI
10.1160/TH11-10-0749
language
English
LU publication?
yes
id
dd0dc83b-b483-4991-b337-7a566418205b (old id 2608501)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22628078?dopt=Abstract
date added to LUP
2012-06-04 20:49:07
date last changed
2017-01-01 05:28:43
@article{dd0dc83b-b483-4991-b337-7a566418205b,
  abstract     = {Farnesyl pyrophosphate (FPP) is an intermediate in cholesterol biosynthesis, and it has also been reported to activate platelet LPA (lysophosphatidic acid) receptors. The aim of this study was to investigate the role of extracellular FPP in platelet aggregation. Human platelets were studied with light transmission aggregometry, flow cytometry and [35S]GTPγS binding assays. As shown previously, FPP could potentiate LPA-stimulated shape change. Surprisingly, FPP also acted as a selective insurmountable antagonist to ADP-induced platelet aggregation. FPP inhibited ADP-induced expression of P-selectin and the activated glycoprotein (Gp)IIb/IIIa receptor. FPP blocked ADP-induced inhibition of cAMP accumulation and [35S]GTPγS binding in platelets. In Chinese hamster ovary cells expressing the P2Y12 receptor, FPP caused a rightward shift of the [35S]GTPγS binding curve. In Sf9 insect cells expressing the human P2Y12 receptor, FPP showed a concentration-dependent, although incomplete inhibition of [3H]PSB-0413 binding. Docking of FPP in a P2Y12 receptor model revealed molecular similarities with ADP and a good fit into the binding pocket for ADP. In conclusion, FPP is an insurmountable antagonist of ADP-induced platelet aggregation mediated by the P2Y12 receptor. It could be an endogenous antithrombotic factor modulating the strong platelet aggregatory effects of ADP in a manner similar to the use of clopidogrel, prasugrel or ticagrelor in the treatment of ischaemic heart disease.},
  author       = {Högberg, Carl and Gidlöf, Olof and Deflorian, F and Jacobson, K A and Abdelrahman, A and Müller, C E and Olde, Björn and Erlinge, David},
  issn         = {0340-6245},
  language     = {eng},
  number       = {1},
  pages        = {119--132},
  publisher    = {F K Schattauer Verlag Gmbh},
  series       = {Thrombosis and Haemostasis},
  title        = {Farnesyl pyrophosphate is an endogenous antagonist to ADP-stimulated P2Y12 receptor-mediated platelet aggregation.},
  url          = {http://dx.doi.org/10.1160/TH11-10-0749},
  volume       = {108},
  year         = {2012},
}