Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK-3β, Resulting in a Loss of Cardiomyocyte Cohesion.
S, P., K, S., E, K., S, M., M, H., S, W., M, R., T, W., A, S., & B, G. (2026). Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK-3β, Resulting in a Loss of Cardiomyocyte Cohesion.. Acta physiologica (Oxford, England). https://doi.org/10.1111/apha.70254
S P, K S, E K, S M, M H, S W, et al. Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK-3β, Resulting in a Loss of Cardiomyocyte Cohesion.. Acta physiologica (Oxford, England). 2026; doi: 10.1111/apha.70254
S P, K S, E K, et al. Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK-3β, Resulting in a Loss of Cardiomyocyte Cohesion.[J]. Acta physiologica (Oxford, England). 2026. DOI: 10.1111/apha.70254.
@article{s2026,
author = {Pathak S and Stangner K and Kempf E and Moztarzadeh S and Hiermaier M and Wider S and Rauschmayer M and Williams T and Stengl A and Gerull B},
title = {Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK-3β, Resulting in a Loss of Cardiomyocyte Cohesion.},
journal = {Acta physiologica (Oxford, England)},
year = {2026},
doi = {10.1111/apha.70254},
note = {PMID: 42219531},
}
TY - JOUR AU - Pathak S AU - Stangner K AU - Kempf E AU - Moztarzadeh S AU - Hiermaier M AU - Wider S AU - Rauschmayer M AU - Williams T AU - Stengl A AU - Gerull B TI - Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK-3β, Resulting in a Loss of Cardiomyocyte Cohesion. T2 - Acta physiologica (Oxford, England) PY - 2026 DO - 10.1111/apha.70254 AN - PMID:42219531 ER -
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac desmosome disease, as more than 50% of affected patients carry pathogenic variants in desmosome protein-coding genes. In this study, we focused on the role and mechanisms of pathogenic and non-pathogenic autoantibodies against intercalated disc (ICD) proteins such as desmoglein2 (DSG2) in ACM patients, healthy relatives (HR), and murine ACM models. MATERIALS AND METHODS: IgG fractions from ACM patients, HR, healthy controls, and murine ACM models were isolated. Besides ELISA and cleavage assay, dissociation assay, immunostaining, Triton-X-100 assay, Western blots, and atomic force microscopy were performed in murine cardiac slices, HL-1 cells, or induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs). RESULTS: IgG fractions from ACM patients and HR, but not murine ACM model-derived or grouped healthy controls IgG (G-HC), revealed positive ICD staining. Three out of six ACM patients derived IgGs that reduced cardiomyocyte cohesion. Pathogenic autoantibodies, bound to DSG2 in healthy and ACM hiPSC-CMs, cleaved and reduced DSG2 interaction at the molecular level. We investigated GSK-3β contribution to the cardiomyocyte cohesion loss and observed GSK-3β reduced baseline cohesion in cultured cardiomyocytes and cardiac slices. Among five ACM-IgGs, three HR-IgGs tested, three pathogenic ACM-IgGs activated GSK-3β upstream of p38MAPK, leading to phosphorylation and junctional loss of β-catenin. GSK-3β inhibition rescued the loss of cell cohesion in ACM hiPSC-CMs. CONCLUSION: Pathogenic autoantibodies targeting DSG2 are present in ACM patients and impair cardiomyocyte cohesion in a GSK-3β-dependent manner. In contrast, autoantibodies are absent in murine ACM models and are non-pathogenic in some patients and HR.