Acta Physiol (Oxf). 2026 Jul;242(7):e70254. doi: 10.1111/apha.70254.
ABSTRACT
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.
PMID:42219531 | DOI:10.1111/apha.70254