Deleting ACC1 in platelets alters phospholipidome and reduces platelet activation and thrombosis in mice

Blood Advances, vol. 9, pp. 4553–4567

Abstract

ABSTRACT: This study uncovers the pivotal role of acetyl-CoA carboxylase 1 (ACC1) in regulating platelet lipid composition, bioenergetics, activation, and thrombus formation, as demonstrated using a targeted glycoprotein Ibα (GPIbα)-Cre+/- mouse model. By comparing platelet-specific ACC1 knockout mice (GPIbα-Cre+/- × ACC1flx/flx) with both GPIbα-Cre+/- and ACC1flx/flx control groups, we showed that ACC1 deficiency profoundly reshaped the platelet phospholipidome. Specifically, ACC1 deletion led to decreased levels of arachidonic acid-containing phosphatidylethanolamine plasmalogens, thereby limiting thromboxane A2 synthesis, dense granule secretion, and platelet activation upon agonist stimulation. Bioenergetic analysis of ACC1-deficient platelets revealed reduced glycolytic activity, potentially worsening their activation defects. Notably, ACC1 deficiency also enhanced the mitochondrial reserve respiratory capacity, without altering basal respiration or adenosine triphosphate turnover. This increased reserve respiratory capacity correlated with reduced phosphatidylserine exposure, suggesting lower procoagulant activity. Importantly, we showed that ACC1 deficiency impaired thrombus formation without compromising hemostasis. Together, these findings identified ACC1 as a critical regulator of platelet function and highlighted its potential as a target for innovative antithrombotic therapies.

Authors 19

1. Marie Octave

   UCLouvain

   Affiliation as printed

   1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   Université catholique de Louvain, Brussels, Belgium

2. Laurence Pirotton

   UCLouvain

   Affiliation as printed

   1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   UCLouvain, Brussels, Belgium

3. Emma de Cartier d’Yves

   UCLouvain

   Affiliation as printed

   1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   Université catholique de Louvain, Brussels, Belgium

4. Alice Marino

   UCLouvain

   Affiliation as printed

   1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   Université catholique de Louvain, Brussels, Belgium

5. Jérôme Ambroise

   UCLouvain

   Affiliation as printed

   2Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   Université catholique de Louvain, Woluwé-St-Lambert, Belgium

6. Martin A. Giera

   Leiden University Medical Center

   Affiliation as printed

   3Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands

   Leiden University Medical Center, Leiden, Netherlands

7. Bruno Guigas

   Leiden University Medical Center

   Affiliation as printed

   4Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

   Leiden University Medical Center, Leiden, Netherlands

8. Audrey Ginion

   UCLouvain

   Affiliation as printed

   1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   UCL, Brussels, Belgium

9. Valentine Robaux

   UCLouvain

   Affiliation as printed

   1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

   UCLouvain, Brussels, Belgium

10. Marijke J. E. Kuijpers

    Maastricht University · Maastricht University Medical Centre

    Affiliation as printed

    5Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    6Thrombosis Expertise Centre, Heart and Vascular Centre, Maastricht University Medical Centre, Maastricht, The Netherlands

    Maastricht University Medical Centre, Netherlands

11. Constance C. F. M. J. Baaten Aachen 7Institute for Molecular Cardiovascular Research

    RWTH Aachen University · Universitätsklinikum Aachen · Maastricht University

    Affiliation as printed

    5Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    7Institute for Molecular Cardiovascular Research, University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany

    University Hospital RWTH Aachen, Aachen, Germany

12. Johan W. M. Heemskerk

    Maastricht University · Synapse (Netherlands)

    Affiliation as printed

    5Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    Synapse Research Institute, Maastricht, Netherlands

13. Zoltán Nagy

    University of Würzburg · Universitätsklinikum Würzburg

    Affiliation as printed

    8Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany

    University Hospital Würzburg, Würzburg, Germany

14. Yotis A. Senis

    Inserm · Université de Strasbourg · Biologie et pharmacologie des plaquettes sanguines : hémostase, thrombose, transfusion · Établissement Français du Sang

    Affiliation as printed

    9INSERM, Etablissement Français du Sang Grand Est, Unité Mixte de Recherche S1255, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, France

    Etablissement Francais du Sang Grand-Est, Strasbourg, France

15. Davide Brusa

    UCLouvain

    Affiliation as printed

    10CytoFlux-Flow Cytometry and Cell Sorting Platform, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

    Université catholique de Louvain, Brussels, Belgium

16. Caroline Bouzin

    UCLouvain

    Affiliation as printed

    11Institut de Recherche Expérimentale et Clinique Imaging Platform (2IP, RRID:SCR_023378), Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

    UCLouvain, Brussels, Belgium

17. Luc Bertrand

    UCLouvain

    Affiliation as printed

    1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

    UCLouvain, Brussels, Belgium

18. Christophe Beauloye

    UCLouvain · Cliniques Universitaires Saint-Luc

    Affiliation as printed

    12Department of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    13Department of Cardiovascular Intensive Care, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

    Cliniques universitaires Saint-Luc, Belgium

19. Sandrine Horman corresponding

    UCLouvain

    Affiliation as printed

    1Pôle de Recherche Cardiovasculaire, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium

    Université catholique de Louvain, Brussels, Belgium