AMPK\u03b11 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism

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

doi:10.1007/s00395-021-00846-y

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.

Highlights

Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide, in spite of improved prevention and therapy [23, 24]
While it is recognised that fibroblast proliferation declines from days 5 to 7 post-myocardial infarction (MI) to give way to the maturation phase, our results suggest that loss of AMPKα1 gene function in MFs promotes and sustains their proliferation in conditional knockout (cKO) infarcts, increasing their number, which underlies the enhanced fibrosis in mice with Postn-mediated MF-specific deletion
We provide evidence that connexin 43 (Cx43) is downregulated in MFs isolated from the acutely injured myocardium, probably contributing to the pro-fibrotic responses

Summary

Introduction

Myocardial infarction (MI) is a major cause of mortality and morbidity worldwide, in spite of improved prevention and therapy [23, 24]. The acute loss of cardiomyocytes is followed by adverse cardiac remodelling because of excessive volume and pressure load on non-infarcted areas. This process encompasses the development of cardiomyocyte hypertrophy, myocardial fibrosis, dilatation, and electrophysiological changes, all leading to left ventricular (LV) dysfunction, and eventually, heart failure and death [18, 24]. As in MI, CFs become activated and respond to changes in their microenvironment by acquiring a wide range of phenotypic profiles [19, 26] They notably differentiate into myofibroblasts (MFs), with enhanced ECM synthesis and smooth muscle-like contractile properties [19]. The fibrotic response proves essential to scar formation and survival in the early post-MI stages, it eventually leads to deleterious adverse LV remodelling in the longer term, both in the infarcted and the remote myocardium [17]

Methods

Results

Conclusion