TY - JOUR
T1 - A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signalling and miRNA dysregulation
AU - Calore, Martina
AU - Lorenzon, Alessandra
AU - Vitiello, Libero
AU - Poloni, Giulia
AU - Khan, Mohsin A. F.
AU - Beffagna, Giorgia
AU - Dazzo, Emanuela
AU - Sacchetto, Claudia
AU - Polishchuk, Roman
AU - Sabatelli, Patrizia
AU - Doliana, Roberto
AU - Carnevale, Daniela
AU - Lembo, Giuseppe
AU - Bonaldo, Paolo
AU - De Windt, Leon
AU - Braghetta, Paola
AU - Rampazzo, Alessandra
N1 - Funding Information:
This work was supported by H2020 Marie Curie Action (MIRAGE) (to M.C.), the University of Padua Strategic Grant TRANSAC CPDA133979/13, Padua, Italy (to A.R.); the Veneto Region Target Research, Venice; the Telethon Grant GGP07220. L.D.W. was supported by grant 311549 from the European Research Council (ERC) and a VICI award 918-156-47 from The Netherlands Organisation for Scientific Research (NWO). We would like to acknowledge Telethon Electron Microscopy Core Facility supported by Telethon grant (GTF08001) to R.P.
Publisher Copyright:
© Published on behalf of the European Society of Cardiology. All rights reserved. The Author(s) 2018. For permissions, please email: [email protected].
PY - 2019/3/15
Y1 - 2019/3/15
N2 - Aims Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern.Methods and results We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/beta-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease.Conclusion Down-regulation of the canonical Wnt/beta-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/beta-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
AB - Aims Arrhythmogenic cardiomyopathy (AC) is one of the most common inherited cardiomyopathies, characterized by progressive fibro-fatty replacement in the myocardium. Clinically, AC manifests itself with ventricular arrhythmias, syncope, and sudden death and shows wide inter- and intra-familial variability. Among the causative genes identified so far, those encoding for the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), and desmoglein-2 (DSG2) are the most commonly mutated. So far, little is known about the molecular mechanism(s) behind such a varied spectrum of phenotypes, although it has been shown that the causative mutations not only lead to structural abnormalities but also affect the miRNA profiling of cardiac tissue. Here, we aimed at studying the pathogenic effects of a nonsense mutation of the desmoglein-2 gene, both at the structural level and in terms of miRNA expression pattern.Methods and results We generated transgenic mice with cardiomyocyte-specific overexpression of a FLAG-tagged human desmoglein-2 harbouring the Q558* nonsense mutation found in an AC patient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/beta-catenin signalling. Genome-wide RNA-Seq performed in Tg-hQ hearts and non-transgenic hearts revealed that 24 miRNAs were dysregulated in transgenic animals. Further bioinformatic analyses for selected miRNAs suggested that miR-217-5p, miR-499-5p, and miR-708-5p might be involved in the pathogenesis of the disease.Conclusion Down-regulation of the canonical Wnt/beta-catenin signalling might be considered a common key event in the AC pathogenesis. We identified the miRNA signature in AC hearts, with miR-708-5p and miR-217-5p being the most up-regulated and miR-499-5p the most down-regulated miRNAs. All of them were predicted to be involved in the regulation of the Wnt/beta-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease.
KW - Arrhythmogenic cardiomyopathy
KW - Molecular pathogenesis
KW - miRNA
KW - RIGHT-VENTRICULAR CARDIOMYOPATHY
KW - CARDIAC DIFFERENTIATION
KW - NUCLEAR PLAKOGLOBIN
KW - INTERCALATED DISKS
KW - STEM-CELLS
KW - CARDIOMYOCYTES
KW - LEADS
KW - PROLIFERATION
KW - ADIPOGENESIS
KW - CONTRIBUTES
U2 - 10.1093/cvr/cvy253
DO - 10.1093/cvr/cvy253
M3 - Article
C2 - 30304392
SN - 0008-6363
VL - 115
SP - 739
EP - 751
JO - Cardiovascular Research
JF - Cardiovascular Research
IS - 4
ER -