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Thromb Haemost 2012; 108(01): 119-132
DOI: 10.1160/TH11-10-0749
Platelets and Blood Cells
Schattauer GmbH

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

Carl Högberg
1   Department of Cardiology, Lund University, Lund, Sweden
,
Olof Gidlöf
1   Department of Cardiology, Lund University, Lund, Sweden
,
Francesca Deflorian
2   National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
,
Kenneth A. Jacobson
2   National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
,
Aliaa Abdelrahman
3   PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
,
Christa E. Müller
3   PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany
,
Björn Olde
1   Department of Cardiology, Lund University, Lund, Sweden
,
David Erlinge
1   Department of Cardiology, Lund University, Lund, Sweden
› Author Affiliations
Further Information

Publication History

Received: 17 November 2011

Accepted after major revision: 20 April 2012

Publication Date:
22 November 2017 (online)

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Summary

Farnesyl pyrophosphate (FPP) is an intermediate in cholesterol biosynthesis, and it has also been reported to activate platelet LPA (lysophos-phatidic 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 right-ward 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.

Keywords

ADP receptors - platelet pharmacology - platelet physiology
 

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