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

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.

• Authors: 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
• Journal: Basic research in cardiology (Basic Res Cardiol) Vol. 116 Issue 1 Pg. 10 (02 09 2021) ISSN: 1435-1803 [Electronic] Germany
• PMID: 33564961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Connexin 43
• GJA1 protein, human
• GJA1 protein, mouse
• MIRN125 microRNA, human
• MicroRNAs
• Mirn125 microRNA, mouse
• AMPK alpha1 subunit, mouse
• AMP-Activated Protein Kinases
• PRKAA1 protein, human

Topics

• AMP-Activated Protein Kinases (deficiency, genetics, metabolism)
• Animals
• Cell Proliferation
• Connexin 43 (genetics, metabolism)
• Disease Models, Animal
• Female
• Fibrosis
• Gene Deletion
• HEK293 Cells
• Humans
• Male
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Myocardial Infarction (enzymology, genetics, pathology, physiopathology)
• Myocardium (enzymology, pathology)
• Myofibroblasts (enzymology, pathology)
• Signal Transduction
• Ventricular Function, Left
• Ventricular Remodeling
• Mice