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

Autor: Caroline Bouzin, Luc Bertrand, Simon J. Conway, Peter Sinnaeve, Audrey Ginion, Bertrand Bearzatto, Jean-Luc Gala, Julien Cumps, Stefan Vinckier, Jean-Luc Balligand, Jérôme Ambroise, Cécile Dufeys, Anna-Pia Papageorgiou, Stefan Janssens, Christophe Beauloye, Sandrine Horman, Diego Castanares-Zapatero, Evangelos-Panagiotis Daskalopoulos, Stephane Heymans, Maarten Vanhaverbeke
Přispěvatelé: UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique, UCL - SSS/IREC/CTMA - Centre de technologies moléculaires appliquées (plate-forme technologique), UCL - (SLuc) Service de médecine interne générale, UCL - (SLuc) Département cardiovasculaire, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy
Rok vydání: 2021
Předmět:
Male
AMPK
Cardiac & Cardiovascular Systems
CROSS-LINKING
Physiology
Cardiac fibrosis
mir-125b-5p
Myocardial Infarction
Connexin
AMPKα
AMP-Activated Protein Kinases
CX43 EXPRESSION
Ventricular Function
Left
connexin 43
Fibrosis
Conditional gene knockout
Medicine
Myocardial infarction
Myofibroblasts
CARDIAC-HYPERTROPHY
Mice
Knockout
Ventricular Remodeling
ACTIVATED PROTEIN-KINASE
Original Contribution
FIBROBLAST
medicine.anatomical_structure
Female
Cardiology and Cardiovascular Medicine
Life Sciences & Biomedicine
Myofibroblast
Signal Transduction
Cardiac fibroblast
CELL-PROLIFERATION
Physiology (medical)
Animals
Humans
Fibroblast
Cell Proliferation
Science & Technology
LEFT-VENTRICULAR DILATION
business.industry
Myocardium
cardiac fibroblast
miR-125b-5p
medicine.disease
DYSFUNCTION
Disease Models
Animal
MicroRNAs
HEK293 Cells
MYOCARDIAL-INFARCTION
AMPKα1
Connexin 43
Cardiovascular System & Cardiology
Cancer research
Ligation
business
Gene Deletion
Zdroj: Basic Research in Cardiology, Vol. 116, no. 10, p. 1-20 (2021)
Basic Research in Cardiology, 116(1):10. Springer
Basic Research in Cardiology
ISSN: 1435-1803
0300-8428
DOI: 10.1007/s00395-021-00846-y
Popis: 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. Supplementary Information The online version contains supplementary material available at 10.1007/s00395-021-00846-y.
Databáze: OpenAIRE
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