Résumé
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.
langue originale | Anglais |
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Numéro d'article | 10 |
journal | Basic Research in Cardiology |
Volume | 116 |
Numéro de publication | 1 |
Les DOIs | |
Etat de la publication | Publié - déc. 2021 |
Modification externe | Oui |
Financement
This work was supported by Grants from Fonds National de la Recherche Scientifique et Médicale (FNRS, Belgium), and Action de Recherche Concertée de la Communauté Wallonie-Bruxelles, Belgium (ARC 13/18-051, ARC 16/21-074), and with unrestricted Grants from Astra Zeneca. CD was supported by a FRIA fellowship (FNRS, Belgium) and by a Bourse du Patrimoine (UCL, Belgium). EPD was supported by a European Society of Cardiology (ESC) Research Grant and by the Fonds de Recherche Clinique (Cliniques Universitaires Saint-Luc, Belgium). SJC was supported by National Institutes of Health Grants HL135657 and HL148165. LB and SH work as senior research associates at FNRS, Belgium.
Bailleurs de fonds | Numéro du bailleur de fonds |
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Action de Recherche Concertée de la Communauté Wallonie-Bruxelles | 13/18-051, ARC 16/21-074 |
Bourse du Patrimoine | |
Fonds National de la Recherche Scientifique et Médicale | |
Fonds de Recherche Clinique | |
National Institute of Child Health and Human Development (NICHD) | HL135657 |
National Institute of Child Health and Human Development (NICHD) | |
National Heart, Lung, and Blood Institute | R01HL148165 |
National Heart, Lung, and Blood Institute | |
AstraZeneca | |
European Society of Cardiology | |
Fonds pour la Formation à la Recherche dans l'Industrie et l'Agriculture | |
Université Catholique de Louvain | |
Cliniques Universitaires Saint-Luc |