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

Carl Högberg; Olof Gidlöf; Francesca Deflorian; Kenneth A. Jacobson; Aliaa Abdelrahman; Christa E. Müller; Björn Olde; David Erlinge

doi:10.1160/TH11-10-0749

Thrombosis and Haemostasis, Table of Contents

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

¹Department of Cardiology, Lund University, Lund, Sweden

,

Olof Gidlöf

¹Department of Cardiology, Lund University, Lund, Sweden

,

Francesca Deflorian

²National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

,

Kenneth A. Jacobson

²National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

,

Aliaa Abdelrahman

³PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany

,

Christa E. Müller

³PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany

,

Björn Olde

¹Department of Cardiology, Lund University, Lund, Sweden

,

David Erlinge

¹Department of Cardiology, Lund University, Lund, Sweden

› Author Affiliations

Abstract

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

Full Text

References

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