Dufeys, CécileDaskalopoulos, Evangelos-PanagiotisCastanares-Zapatero, DiegoConway, Simon J.Ginion, AudreyBouzin, CarolineAmbroise, JérômeBearzatto, BertrandGala, Jean-LucHeymans, StephanePapageorgiou, Anna-PiaVinckier, StefanCumps, JulienBalligand, Jean-LucVanhaverbeke, MaartenSinnaeve, PeterJanssens, StefanBertrand, LucBeauloye, ChristopheHorman, Sandrine2022-05-172022-05-172021-02-09Dufeys C, Daskalopoulos EP, Castanares-Zapatero D, et al. AMPKα1 deletion in myofibroblasts exacerbates post-myocardial infarction fibrosis by a connexin 43 mechanism. Basic Res Cardiol. 2021;116(1):10. Published 2021 Feb 9. doi:10.1007/s00395-021-00846-yhttps://hdl.handle.net/1805/29046We 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.en-USAttribution 4.0 InternationalCardiac fibrosisCardiac fibroblastMyofibroblastAMPKα1Connexin 43miR-125b-5pArticle