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

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-beta 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/beta-catenin signaling and intercellular adhesion.