Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate <scp>GSK</scp> ‐3β, Resulting in a Loss of Cardiomyocyte Cohesion

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.