BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations, whose pathogenesis remains incompletely understood.OBJECTIVE: 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 over-expressing 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. Pharmacological inhibition of Lgals3 in zebrafish reduced Wnt and TGFbeta 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 GAL3 release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions.CONCLUSIONS: GAL3 plays a crucial role in early AC onset through regulation of Wnt/beta-catenin signaling and intercellular adhesion.

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

Cason, Marco
Writing – Original Draft Preparation
;
Celeghin, Rudy
Methodology
;
Marinas, Maria Bueno
Methodology
;
Beffagna, Giorgia
Validation
;
Rizzo, Stefania
Methodology
;
Tiso, Natascia
Methodology
;
Bauce, Barbara
Visualization
;
Thiene, Gaetano
Membro del Collaboration Group
;
Basso, Cristina
Membro del Collaboration Group
;
Pilichou, Kalliopi
Conceptualization
2021

Abstract

BACKGROUND: Arrhythmogenic cardiomyopathy (AC) is a myocardial disease due to desmosomal mutations, whose pathogenesis remains incompletely understood.OBJECTIVE: 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 over-expressing 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. Pharmacological inhibition of Lgals3 in zebrafish reduced Wnt and TGFbeta 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 GAL3 release by circulating macrophages pointing toward the stabilization of desmosomal assembly at the injured regions.CONCLUSIONS: GAL3 plays a crucial role in early AC onset through regulation of Wnt/beta-catenin signaling and intercellular adhesion.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3388808
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