Martina Calore1,2, Alessandra Lorenzon1, Libero Vitiello1,3, Giulia Poloni1, Mohsin A F Khan4, Giorgia Beffagna1, Emanuela Dazzo1, Claudia Sacchetto1, Roman Polishchuk5, Patrizia Sabatelli6, Roberto Doliana7, Daniela Carnevale8,9, Giuseppe Lembo8,9, Paolo Bonaldo10, Leon De Windt2, Paola Braghetta10, Alessandra Rampazzo1. 1. Department of Biology, University of Padua, Via Ugo Bassi 58/B, Padua, Italy. 2. Department of Cardiology, Faculty of Health, Medicine and Life Sciences, Maastricht University, MD Maastricht, The Netherlands. 3. Italian Inter-University Institute of Myology, Padua, Italy. 4. Department of Experimental Cardiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands. 5. Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy. 6. National Research Council of Italy, Institute of Molecular Genetics, Bologna, Italy. 7. Department of Translational Research, CRO-IRCCS National Cancer Institute, Aviano, Italy. 8. Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy. 9. Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. 10. Department of Molecular Medicine, University of Padua, Via Ugo Bassi 58/B, Padua, Italy.
Abstract
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/β-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/β-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/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease. Published on behalf of the European Society of Cardiology. All rights reserved.
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 humandesmoglein-2 harbouring the Q558* nonsense mutation found in an ACpatient. The hearts of these mice showed signs of fibrosis, decrease in desmosomal size and number, and reduction of the Wnt/β-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/β-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/β-catenin pathway and might reveal the potential pathophysiology mechanisms of AC, as well as be useful as therapeutic targets for the disease. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Chantal J M van Opbergen; Maartje Noorman; Anna Pfenniger; Jaël S Copier; Sarah H Vermij; Zhen Li; Roel van der Nagel; Mingliang Zhang; Jacques M T de Bakker; Aaron M Glass; Peter J Mohler; Steven M Taffet; Marc A Vos; Harold V M van Rijen; Mario Delmar; Toon A B van Veen Journal: Int J Mol Sci Date: 2019-08-21 Impact factor: 5.923
Authors: Aleksandr A Khudiakov; Daniil D Panshin; Yulia V Fomicheva; Anastasia A Knyazeva; Ksenia A Simonova; Dmitry S Lebedev; Evgeny N Mikhaylov; Anna A Kostareva Journal: Front Cardiovasc Med Date: 2021-03-19