Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy

• DOI: 10.1172/jci.insight.85923
• Publication Date: 2016-04-20T15:01:01Z
• Authors: Stephen P. Chelko; Angeliki Asimaki; Peter Andersen; Djahida Bedja; Nuria Amat-Alarcon; Deeptankar DeMazu...; Ravirasmi Jasti; Calum A. MacRae; Remo Leber; Andre G. Kleber; Jeffrey E. Saffitz; Daniel P. Judge
• Keywords: Desmosome; Pathogenesis; Myocardial fibrosis

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 zebrafish model ACM. Here, we show SB2 prevents myocyte injury cardiac dysfunction vivo two murine models ACM at baseline response to exercise. SB2-treated mice with desmosome mutations showed improvements ventricular ectopy fibrosis/inflammation compared vehicle-treated (Veh-treated) mice. inhibition improved left ventricle function survival sedentary exercised Dsg2mut/mut Veh-treated normalized intercalated disc (ID) protein distribution both mutant diffuse cytoplasmic localization control myocytes but ID Identical present patient myocardium not normal hearts or other cardiomyopathies. reduced total levels phosphorylated Ser 9-GSK3β Constitutively active worsens mice, while shRNA silencing cardiomyocytes abnormal distribution. These results highlight central role for GSKβ the complex phenotype provide further evidence pharmacologic improves cardiomyopathies due mutations.