title: Molecular disturbance underlies to arrhythmogenic cardiomyopathy induced by transgene content, age and exercise in a truncated PKP2 mouse model.
abstract: Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for >40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibro-fatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and β-Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Nav1.5). Surprisingly, we observed structural but not electrophysiological abnormalities only in trained and old mice. We demonstrated that truncated PKP2 provokes ACM in the absence of fibro-fatty replacement in the mouse. Transgene dose is essential to reveal the pathology, whereas aging and endurance training trigger limited phenotype. Molecular abnormalities underlay the structural and electrophysiological defects.
authors.affiliation: Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain.|Department of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Moncayo-Arlandi
authors.affiliation: Arrhythmia Unit, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS.
authors.forename: Eduard
authors.initials: E
authors.lastname: Guasch
authors.affiliation: Imaging Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Sanz-de la Garza
authors.affiliation: Institute of Biomedicine of Valencia, IBV-CSIC, Valencia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Casado
authors.affiliation: Mixed unit for Cardiovascular Repair, Instituto de Investigación Sanitaria La Fe-Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Nahuel Aquiles
authors.initials: NA
authors.lastname: Garcia
authors.affiliation: Arrhythmia Unit, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS.
authors.forename: Lluis
authors.initials: L
authors.lastname: Mont
authors.affiliation: Imaging Section, Cardiology Department, Hospital Clínic, Universitat de Barcelona and IDIBAPS, Barcelona, Catalonia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Sitges
authors.affiliation: Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden.
authors.forename: Ralph
authors.initials: R
authors.lastname: Knöll
authors.affiliation: Department of Medicine, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden.
authors.forename: Byambajav
authors.initials: B
authors.lastname: Buyandelger
authors.affiliation: Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain.|Medical Science Department, School of Medicine, University of Girona.
authors.forename: Oscar
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Fundación IVI/INCLIVA and IGENOMIX, Valencia, Spain rbrugada@idibgi.org.
authors.forename: Antonio
authors.initials: A
authors.lastname: Diez-Juan
authors.affiliation: Cardiovascular Genetic Centre, Institute of Biomedical Research of Girona (IDIBGI), Girona, Spain, rbrugada@idibgi.org.|Medical Science Department, School of Medicine, University of Girona.|Cardiovascular Genetics Clinic, Hospital Josep Trueta, Girona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051379:Mice; D009154:Mutation; D010807:Physical Endurance / Q000502:physiology*; D051191:Plakophilins / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes
chemical_list: C495338:Pkp2 protein, mouse; D051191:Plakophilins