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Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK‐3β, Resulting in a Loss of Cardiomyocyte Cohesion.

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Title: Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK‐3β, Resulting in a Loss of Cardiomyocyte Cohesion.
Authors: Pathak, Soumyata (AUTHOR), Stangner, Konstanze (AUTHOR), Kempf, Ellen (AUTHOR), Moztarzadeh, Sina (AUTHOR), Hiermaier, Matthias (AUTHOR), Wider, Stephanie (AUTHOR), Rauschmayer, Marlene (AUTHOR), Williams, Tatjana (AUTHOR), Stengl, Andreas (AUTHOR), Gerull, Brenda (AUTHOR), Biller, Ruth (AUTHOR), Clauss, Sebastian (AUTHOR), Kääb, Stefan (AUTHOR), Šarić, Tomo (AUTHOR), Yeruva, Sunil (AUTHOR), Waschke, Jens (AUTHOR)
Source: Acta Physiologica. Jul2026, Vol. 242 Issue 7, p1-20. 20p.
Subjects: Autoantibodies, Glycogen synthase kinase-3, Desmogleins, Cell adhesion, Cell junctions, Arrhythmogenic right ventricular dysplasia, Catenins
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. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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DbLabel: Psychology and Behavioral Sciences Collection
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  Data: Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK‐3β, Resulting in a Loss of Cardiomyocyte Cohesion.
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  Data: <searchLink fieldCode="AR" term="%22Pathak%2C+Soumyata%22">Pathak, Soumyata</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Stangner%2C+Konstanze%22">Stangner, Konstanze</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kempf%2C+Ellen%22">Kempf, Ellen</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Moztarzadeh%2C+Sina%22">Moztarzadeh, Sina</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Hiermaier%2C+Matthias%22">Hiermaier, Matthias</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wider%2C+Stephanie%22">Wider, Stephanie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Rauschmayer%2C+Marlene%22">Rauschmayer, Marlene</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Williams%2C+Tatjana%22">Williams, Tatjana</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Stengl%2C+Andreas%22">Stengl, Andreas</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Gerull%2C+Brenda%22">Gerull, Brenda</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Biller%2C+Ruth%22">Biller, Ruth</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Clauss%2C+Sebastian%22">Clauss, Sebastian</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kääb%2C+Stefan%22">Kääb, Stefan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Šarić%2C+Tomo%22">Šarić, Tomo</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yeruva%2C+Sunil%22">Yeruva, Sunil</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Waschke%2C+Jens%22">Waschke, Jens</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. Jul2026, Vol. 242 Issue 7, p1-20. 20p.
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  Data: <searchLink fieldCode="DE" term="%22Autoantibodies%22">Autoantibodies</searchLink><br /><searchLink fieldCode="DE" term="%22Glycogen+synthase+kinase-3%22">Glycogen synthase kinase-3</searchLink><br /><searchLink fieldCode="DE" term="%22Desmogleins%22">Desmogleins</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+adhesion%22">Cell adhesion</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+junctions%22">Cell junctions</searchLink><br /><searchLink fieldCode="DE" term="%22Arrhythmogenic+right+ventricular+dysplasia%22">Arrhythmogenic right ventricular dysplasia</searchLink><br /><searchLink fieldCode="DE" term="%22Catenins%22">Catenins</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/apha.70254
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        Text: English
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      – SubjectFull: Autoantibodies
        Type: general
      – SubjectFull: Glycogen synthase kinase-3
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      – SubjectFull: Desmogleins
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      – SubjectFull: Catenins
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      – TitleFull: Autoantibodies in Patients With Arrhythmogenic Cardiomyopathy Activate GSK‐3β, Resulting in a Loss of Cardiomyocyte Cohesion.
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              Text: Jul2026
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