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

• Published in: Basic research in cardiology 2021-12, Vol.116 (1), p.10, Article 10
• Main Authors: 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, Sandrine
• Format: Article
• Language: English
• Subjects: AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - deficiency; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Cardiology; Cell Proliferation; Connexin 43; Connexin 43 - genetics; Connexin 43 - metabolism; Coronary artery; Deletion; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Gene Deletion; Heart; Heart attacks; HEK293 Cells; Humans; Kinases; Male; Medicine; Medicine & Public Health; Mice; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Molecular modelling; Myocardial infarction; Myocardial Infarction - enzymology; Myocardial Infarction - genetics; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium; Myocardium - enzymology; Myocardium - pathology; Myofibroblasts - enzymology; Myofibroblasts - pathology; Original Contribution; Post-transcription; Signal Transduction; Ventricle; Ventricular Function, Left; Ventricular Remodeling
• ISSN: 0300-8428; 1435-1803
• DOI: 10.1007/s00395-021-00846-y

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.