AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism.

Autor: Dufeys C; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium., Daskalopoulos EP; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium., Castanares-Zapatero D; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium., Conway SJ; HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA., Ginion A; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium., Bouzin C; IREC Imaging Platform, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium., Ambroise J; Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, UCL, Brussels, Belgium., Bearzatto B; Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, UCL, Brussels, Belgium., Gala JL; Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, UCL, Brussels, Belgium., Heymans S; Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands., Papageorgiou AP; Center for Heart Failure Research, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.; Department of Cardiovascular Sciences, KU Leuven, Louvain, Belgium., Vinckier S; Center for Cancer Biology, University of Leuven and VIB, Louvain, Belgium., Cumps J; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium., Balligand JL; Pôle de Pharmacologie et de Thérapeutique (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), Brussels, Belgium., Vanhaverbeke M; Department of Cardiovascular Sciences, KU Leuven, Louvain, Belgium.; Department of Cardiovascular Medicine, Leuven University Hospitals, Louvain, Belgium., Sinnaeve P; Department of Cardiovascular Sciences, KU Leuven, Louvain, Belgium.; Department of Cardiovascular Medicine, Leuven University Hospitals, Louvain, Belgium., Janssens S; Department of Cardiovascular Sciences, KU Leuven, Louvain, Belgium.; Department of Cardiovascular Medicine, Leuven University Hospitals, Louvain, Belgium., Bertrand L; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium., Beauloye C; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium.; Division of Cardiology, Cliniques Universitaires Saint-Luc, Brussels, Belgium., Horman S; Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 55, Avenue Hippocrate, 1200, Brussels, Belgium. sandrine.horman@uclouvain.be.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2021 Feb 09; Vol. 116 (1), pp. 10. Date of Electronic Publication: 2021 Feb 09.
DOI: 10.1007/s00395-021-00846-y
Abstrakt: We have previously demonstrated that systemic AMP-activated protein kinase α1 (AMPKα1) invalidation enhanced adverse LV remodelling by increasing fibroblast proliferation, while myodifferentiation and scar maturation were impaired. We thus hypothesised that fibroblastic AMPKα1 was a key signalling element in regulating fibrosis in the infarcted myocardium and an attractive target for therapeutic intervention. The present study investigates the effects of myofibroblast (MF)-specific deletion of AMPKα1 on left ventricular (LV) adaptation following myocardial infarction (MI), and the underlying molecular mechanisms. MF-restricted AMPKα1 conditional knockout (cKO) mice were subjected to permanent ligation of the left anterior descending coronary artery. cKO hearts exhibit exacerbated post-MI adverse LV remodelling and are characterised by exaggerated fibrotic response, compared to wild-type (WT) hearts. Cardiac fibroblast proliferation and MF content significantly increase in cKO infarcted hearts, coincident with a significant reduction of connexin 43 (Cx43) expression in MFs. Mechanistically, AMPKα1 influences Cx43 expression by both a transcriptional and a post-transcriptional mechanism involving miR-125b-5p. Collectively, our data demonstrate that MF-AMPKα1 functions as a master regulator of cardiac fibrosis and remodelling and might constitute a novel potential target for pharmacological anti-fibrotic applications.
Databáze: MEDLINE
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