Novel pathogenic role for galectin-3 in early disease stages of arrhythmogenic cardiomyopathy.

Animals Arrhythmogenic Right Ventricular Dysplasia / genetics DNA / genetics DNA Mutational Analysis Disease Models, Animal Galectin 3 / genetics Mice Mice, Transgenic Mutation Phenotype
Arrhythmogenic cardiomyopathy Gene expression Inflammation LGALS3 Transgenic models Wnt signaling

Journal

Heart rhythm
ISSN: 1556-3871
Titre abrégé: Heart Rhythm
Pays: United States
ID NLM: 101200317

Informations de publication

Date de publication:
08 2021
Historique:
received: 28 09 2020
revised: 23 03 2021
accepted: 05 04 2021
pubmed: 16 4 2021
medline: 12 2 2022
entrez: 15 4 2021
Statut: ppublish

Résumé

Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations whose pathogenesis is incompletely understood. The purpose of this study was to identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models. RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice overexpressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for in vivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases. Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacologic inhibition of Lgals3 in zebrafish reduced Wnt and transforming growth factor-β signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the galectin-3 (GAL3) release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions. GAL3 plays a crucial role in early AC onset through regulation of Wnt/β-catenin signaling and intercellular adhesion.

Sections du résumé

BACKGROUND
Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations whose pathogenesis is incompletely understood.
OBJECTIVE
The purpose of this study was to identify molecular pathways underlying early AC by gene expression profiling in both humans and animal models.
METHODS
RNA sequencing for differentially expressed genes (DEGs) was performed on the myocardium of transgenic mice overexpressing the Desmoglein2-N271S mutation before phenotype onset. Zebrafish signaling reporters were used for in vivo validation. Whole exome sequencing was undertaken in 10 genotype-negative AC patients and subsequent direct sequencing in 140 AC index cases.
RESULTS
Among 29 DEGs identified at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) showed reduced cardiac expression in transgenic mice and in 3 AC patients who suffered sudden cardiac death without overt structural remodeling. Four rare missense variants of LGALS3 were identified in 5 human AC probands. Pharmacologic inhibition of Lgals3 in zebrafish reduced Wnt and transforming growth factor-β signaling, increased Hippo/YAP-TAZ signaling, and induced alterations in desmoplakin membrane localization, desmosome integrity and stability. Increased LGALS3 plasma expression in genotype-positive AC patients and CD98 activation supported the galectin-3 (GAL3) release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions.
CONCLUSION
GAL3 plays a crucial role in early AC onset through regulation of Wnt/β-catenin signaling and intercellular adhesion.

Identifiants

DOI: 10.1016/j.hrthm.2021.04.006 PMID: 33857645
pubmed: 33857645
pii: S1547-5271(21)00329-5
doi: 10.1016/j.hrthm.2021.04.006
pii:
doi:

Substances chimiques

Galectin 3 0
DNA 9007-49-2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1394-1403

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Auteurs

Marco Cason (M)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Rudy Celeghin (R)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Maria Bueno Marinas (MB)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Giorgia Beffagna (G)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Mila Della Barbera (M)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Stefania Rizzo (S)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Carol Ann Remme (CA)

Department of Experimental Cardiology, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands.

Connie R Bezzina (CR)

Department of Experimental Cardiology, Amsterdam UMC, location AMC, University of Amsterdam, Amsterdam, The Netherlands.

Natascia Tiso (N)

Department of Biology, University of Padua, Padua, Italy.

Barbara Bauce (B)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Gaetano Thiene (G)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

Cristina Basso (C)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy. Electronic address: cristina.basso@unipd.it.

Kalliopi Pilichou (K)

Cardiovascular Pathology and Cardiology Units, Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Malformations › Malformations cardiovasculaires › Cardiopathies congénitales › Dysplasie ventriculaire droite arythmogène › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Analyse de mutations d'ADN › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Lectines › Galectines › Galectine -3 › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Novel pathogenic role for galectin-3 in early...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Novel pathogenic role for galectin-3 in early...