title: Reduced scar maturation and contractility lead to exaggerated left ventricular dilation after myocardial infarction in mice lacking AMPKα1.
abstract: Cardiac fibroblasts (CF) are crucial in left ventricular (LV) healing and remodeling after myocardial infarction (MI). They are typically activated into myofibroblasts that express alpha-smooth muscle actin (α-SMA) microfilaments and contribute to the formation of contractile and mature collagen scars that minimize the adverse dilatation of infarcted areas. CF predominantly express the α1 catalytic subunit of AMP-activated protein kinase (AMPKα1), while AMPKα2 is the major catalytic isoform in cardiomyocytes. AMPKα2 is known to protect the heart by preserving the energy charge of cardiac myocytes during injury, but whether AMPKα1 interferes with maladaptative heart responses remains unexplored. In this study, we investigated the role of AMPKα1 in modulating LV dilatation and CF fibrosis during post-MI remodeling. AMPKα1 knockout (KO) and wild type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery. The absence of AMPKα1 was associated with increased CF proliferation in infarcted areas, while expression of the myodifferentiation marker α-SMA was decreased. Faulty maturation of myofibroblasts might derive from severe down-regulation of the non-canonical transforming growth factor-beta1/p38 mitogen-activated protein kinase (TGF-β1/p38 MAPK) pathway in KO infarcts. In addition, lysyl oxidase (LOX) protein expression was dramatically reduced in the scar of KO hearts. Although infarct size was similar in AMPK-KO and WT hearts subjected to MI, these changes resulted in compromised scar contractility, defective scar collagen maturation, and exacerbated adverse remodeling, as indicated by increased LV diastolic dimension 30days after MI. Our data genetically demonstrate the centrality of AMPKα1 in post-MI scar formation and highlight the specificity of this catalytic isoform in cardiac fibroblast/myofibroblast biology.
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: Gauthier.noppe@uclouvain.be.
authors.forename: Gauthier
authors.initials: G
authors.lastname: Noppe
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: cecile.dufeys@uclouvain.be.
authors.forename: Cécile
authors.initials: C
authors.lastname: Dufeys
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: patricia.buchlin@uclouvain.be.
authors.forename: Patricia
authors.initials: P
authors.lastname: Buchlin
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: nicolas.marquet@uclouvain.be.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Marquet
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: diego.castanares@uclouvain.be.
authors.forename: Diego
authors.initials: D
authors.lastname: Castanares-Zapatero
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: magali.balteau@uclouvain.be.
authors.forename: Magali
authors.initials: M
authors.lastname: Balteau
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Pharmacologie et Thérapeutique, Université catholique de Louvain, Brussels, Belgium. Electronic address: nerea.hermida@uclouvain.be.
authors.forename: Nerea
authors.initials: N
authors.lastname: Hermida
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Pharmacologie et Thérapeutique, Université catholique de Louvain, Brussels, Belgium. Electronic address: caroline.bouzin@uclouvain.be.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouzin
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Pharmacologie et Thérapeutique, Université catholique de Louvain, Brussels, Belgium. Electronic address: hrag.esfahani@uclouvain.be.
authors.forename: Hrag
authors.initials: H
authors.lastname: Esfahani
authors.affiliation: Institut Cochin, INSERM U1016, Paris, France; CNRS, UMR8104, Paris, France; Université Paris Descartes, Sorbonne, Paris Cité, France. Electronic address: benoit.viollet@inserm.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: luc.bertrand@uclouvain.be.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Pharmacologie et Thérapeutique, Université catholique de Louvain, Brussels, Belgium. Electronic address: jean-luc.balligand@uclouvain.be.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium; Cardiology Division, Department of Cardiovascular Diseases, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address: jean-louis.vanoverschelde@uclouvain.be.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium; Cardiology Division, Department of Cardiovascular Diseases, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Cardiovascular Intensive Care, Department of Cardiovascular Diseases, Cliniques Universitaires Saint-Luc, Brussels, Belgium. Electronic address: christophe.beauloye@uclouvain.be.
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
authors.affiliation: Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Université catholique de Louvain, Brussels, Belgium. Electronic address: sandrine.horman@uclouvain.be.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D002921:Cicatrix / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000473:pathology; D058628:Myofibroblasts / Q000201:enzymology* / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D016326:Extracellular Matrix Proteins; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; C077112:Lox protein, mouse; D008249:Protein-Lysine 6-Oxidase; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Cardiac fibroblast; Myocardial infarction; Myodifferentiation; Scar maturation