title: Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy.
abstract: Arrhythmogenic cardiomyopathy (ACM) is characterized by redistribution of junctional proteins, arrhythmias, and progressive myocardial injury. We previously reported that SB216763 (SB2), annotated as a GSK3β inhibitor, reverses disease phenotypes in a zebrafish model of ACM. Here, we show that SB2 prevents myocyte injury and cardiac dysfunction in vivo in two murine models of ACM at baseline and in response to exercise. SB2-treated mice with desmosome mutations showed improvements in ventricular ectopy and myocardial fibrosis/inflammation as compared with vehicle-treated (Veh-treated) mice. GSK3β inhibition improved left ventricle function and survival in sedentary and exercisedDsg2mut/mutmice compared with Veh-treatedDsg2mut/mutmice and normalized intercalated disc (ID) protein distribution in both mutant mice. GSK3β showed diffuse cytoplasmic localization in control myocytes but ID redistribution in ACM mice. Identical GSK3β redistribution is present in ACM patient myocardium but not in normal hearts or other cardiomyopathies. SB2 reduced total GSK3β protein levels but not phosphorylated Ser 9-GSK3β in ACM mice. Constitutively active GSK3β worsens ACM in mutant mice, while GSK3β shRNA silencing in ACM cardiomyocytes prevents abnormal ID protein distribution. These results highlight a central role for GSKβ in the complex phenotype of ACM and provide further evidence that pharmacologic GSKβ inhibition improves cardiomyopathies due to desmosome mutations.
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Chelko
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia.
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Nuria
authors.initials: N
authors.lastname: Amat-Alarcon
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Deeptankar
authors.initials: D
authors.lastname: DeMazumder
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Ravirasmi
authors.initials: R
authors.lastname: Jasti
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.affiliation: Schiller AG, Research and Development, Baar, Switzerland.
authors.forename: Remo
authors.initials: R
authors.lastname: Leber
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Kleber
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.affiliation: Department of Medicine/Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Judge