A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signaling and miRNA dysregulation

Martina Calore, Alessandra Lorenzon, Libero Vitiello, Giulia Poloni, Mohsin A F Khan, Giorgia Beffagna, Emanuela Dazzo, Claudia Sacchetto, Roman Polishchuk, Patrizia Sabatelli, Roberto Doliana, Daniela Carnevale, Giuseppe Lembo, Paolo Bonaldo, Leon De Windt, Paola Braghetta, Alessandra Rampazzo

Research output: Contribution to journalArticle

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 harboring 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 signaling. 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.

Conclusions: Downregulation of the canonical Wnt/β-catenin signaling 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 upregulated and miR-499-5p the most downregulated 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.

Original languageEnglish
JournalCardiovascular Research
DOIs
Publication statusE-pub ahead of print - Oct 10 2018

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MicroRNAs
Cardiomyopathies
Desmoglein 2
Catenins
Nonsense Codon
Plakophilins
Down-Regulation
Desmoplakins
Genetically Modified Animals
Wnt Signaling Pathway
Syncope
Sudden Death
Computational Biology
Cardiac Myocytes
Transgenic Mice
Genes
Cardiac Arrhythmias
Myocardium
Fibrosis
Genome

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A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signaling and miRNA dysregulation. / Calore, Martina; Lorenzon, Alessandra; Vitiello, Libero; Poloni, Giulia; Khan, Mohsin A F; Beffagna, Giorgia; Dazzo, Emanuela; Sacchetto, Claudia; Polishchuk, Roman; Sabatelli, Patrizia; Doliana, Roberto; Carnevale, Daniela; Lembo, Giuseppe; Bonaldo, Paolo; De Windt, Leon; Braghetta, Paola; Rampazzo, Alessandra.

In: Cardiovascular Research, 10.10.2018.

Research output: Contribution to journalArticle

Calore, M, Lorenzon, A, Vitiello, L, Poloni, G, Khan, MAF, Beffagna, G, Dazzo, E, Sacchetto, C, Polishchuk, R, Sabatelli, P, Doliana, R, Carnevale, D, Lembo, G, Bonaldo, P, De Windt, L, Braghetta, P & Rampazzo, A 2018, 'A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signaling and miRNA dysregulation', Cardiovascular Research. https://doi.org/10.1093/cvr/cvy253
Calore, Martina ; Lorenzon, Alessandra ; Vitiello, Libero ; Poloni, Giulia ; Khan, Mohsin A F ; Beffagna, Giorgia ; Dazzo, Emanuela ; Sacchetto, Claudia ; Polishchuk, Roman ; Sabatelli, Patrizia ; Doliana, Roberto ; Carnevale, Daniela ; Lembo, Giuseppe ; Bonaldo, Paolo ; De Windt, Leon ; Braghetta, Paola ; Rampazzo, Alessandra. / A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signaling and miRNA dysregulation. In: Cardiovascular Research. 2018.
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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 harboring 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 signaling. 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.Conclusions: Downregulation of the canonical Wnt/β-catenin signaling 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 upregulated and miR-499-5p the most downregulated 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.",
author = "Martina Calore and Alessandra Lorenzon and Libero Vitiello and Giulia Poloni and Khan, {Mohsin A F} and Giorgia Beffagna and Emanuela Dazzo and Claudia Sacchetto and Roman Polishchuk and Patrizia Sabatelli and Roberto Doliana and Daniela Carnevale and Giuseppe Lembo and Paolo Bonaldo and {De Windt}, Leon and Paola Braghetta and Alessandra Rampazzo",
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T1 - A novel murine model for arrhythmogenic cardiomyopathy points to a pathogenic role of Wnt signaling 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

PY - 2018/10/10

Y1 - 2018/10/10

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 harboring 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 signaling. 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.Conclusions: Downregulation of the canonical Wnt/β-catenin signaling 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 upregulated and miR-499-5p the most downregulated 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.

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 harboring 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 signaling. 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.Conclusions: Downregulation of the canonical Wnt/β-catenin signaling 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 upregulated and miR-499-5p the most downregulated 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.

U2 - 10.1093/cvr/cvy253

DO - 10.1093/cvr/cvy253

M3 - Article

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

ER -