AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism
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Published:2021-02-09
Issue:1
Volume:116
Page:
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ISSN:0300-8428
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Container-title:Basic Research in Cardiology
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language:en
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Short-container-title:Basic Res Cardiol
Author:
Dufeys Cécile, Daskalopoulos Evangelos-Panagiotis, Castanares-Zapatero Diego, Conway Simon J., Ginion Audrey, Bouzin Caroline, Ambroise Jérôme, Bearzatto Bertrand, Gala Jean-Luc, Heymans Stephane, Papageorgiou Anna-Pia, Vinckier Stefan, Cumps Julien, Balligand Jean-Luc, Vanhaverbeke Maarten, Sinnaeve Peter, Janssens Stefan, Bertrand Luc, Beauloye Christophe, Horman SandrineORCID
Abstract
AbstractWe 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.
Funder
Fonds De La Recherche Scientifique - FNRS Action de Recherche Concertée Astra Zeneca Belgium National Institutes of Health grants
Publisher
Springer Science and Business Media LLC
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
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