Influence of Antiplatelet Agents on the Lipid Composition of Platelet Plasma Membrane: A Lipidomics Approach with Ticagrelor and Its Active Metabolite.

Jennifer Lagoutte-Renosi,Siamak Davani,Florentin Allemand,Vahideh Rabani,Christophe Ramseyer

doi:10.3390/ijms22031432

Abstract

Lipids contained in the plasma membrane of platelets play an important role in platelet function. Modifications in the lipid composition can fluidify or rigidify the environment around embedded receptors, in order to facilitate the access of the receptor by the drug. However, data concerning the lipid composition of platelet plasma membrane need to be updated. In addition, data on the impact of drugs on plasma membrane composition, in particular antiplatelet agents, remain sparse. After isolation of platelet plasma membrane, we assessed, using lipidomics, the effect of ticagrelor, a P2Y12 antagonist, and its active metabolite on the lipid composition of these plasma membranes. We describe the exact lipid composition of plasma membrane, including all sub-species. Ticagrelor and its active metabolite significantly increased cholesterol and phosphatidylcholine ether with short saturated acyl chains 16:0/16:0, and decreased phosphatidylcholine, suggesting overall rigidification of the membrane. Furthermore, ticagrelor and its active metabolite decreased some arachidonylated plasmalogens, suggesting a decrease in availability of arachidonic acid from the membrane phospholipids for synthesis of biologically active mediators. To conclude, ticagrelor and its active metabolite seem to influence the lipid environment of receptors embedded in the lipid bilayer and modify the behavior of the plasma membrane.

Highlights

Blood platelets play a pivotal role as regulators of haemostasis and thrombosis [1].The platelet plasma membrane, composed of a lipid bilayer with embedded proteins, is the support for adhesion, activation and aggregation of platelets through receptors [2].G-protein coupled seven-transmembrane P2Y12 receptors belonging to the transmembrane proteins are present in the platelet plasma membrane
Human healthy platelets were studied in 6 experimental groups: (i) a control group, (ii) platelets activated by adenosine diphosphate (ADP) 20 μM, (iii) platelets treated by ticagrelor 1.5 μM, (iv) platelets treated by ticagrelor active metabolite (AR-C124910XX, 0.5 μM), (v) platelets treated by ticagrelor 1.5 μM for 10 min by ADP 20 μM for 10 min, and (vi) platelets treated by ticagrelor active metabolite 0.5 μM for 10 min by ADP 20 μM for 10 min
This study shows that antiplatelet agents, such as ticagrelor and its active metabolite, modify the lipid composition of platelet plasma membrane

Summary

Introduction

G-protein coupled seven-transmembrane P2Y12 receptors belonging to the transmembrane proteins are present in the platelet plasma membrane. Platelet aggregation contributes to the onset of acute coronary syndrome, and current guidelines recommend dual antiplatelet therapy, including a P2Y12 antagonist and aspirin, for at least 12 months after the cardiovascular event [4]. In this context, P2Y12 antagonists such as clopidogrel, ticagrelor and prasugrel were developed to prevent cardiovascular events, especially after acute coronary syndrome

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