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

Cécile Dufeys, Evangelos Panagiotis Daskalopoulos, Diego Castanares-Zapatero, Simon J. Conway, Audrey Ginion, Caroline Bouzin, Jérôme Ambroise, Bertrand Bearzatto, Jean Luc Gala, Stephane Heymans, Anna Pia Papageorgiou, Stefan Vinckier, Julien Cumps, Jean Luc Balligand, Maarten Vanhaverbeke, Peter Sinnaeve, Stefan Janssens, Luc Bertrand, Christophe Beauloye, Sandrine Horman

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number10
JournalBasic Research in Cardiology
Volume116
Issue number1
DOIs
Publication statusPublished - Dec 2021
Externally publishedYes

Keywords

  • AMPKα1
  • Cardiac fibroblast
  • Cardiac fibrosis
  • Connexin 43
  • miR-125b-5p
  • Myofibroblast

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