Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy
Stephen P. Chelko, Angeliki Asimaki, Peter Andersen, Djahida Bedja, Nuria Amat-Alarcon, Deeptankar DeMazumder, Ravirasmi Jasti, Calum A. MacRae, Remo Leber, Andre G. Kleber, Jeffrey E. Saffitz, Daniel P. Judge
Stephen P. Chelko, Angeliki Asimaki, Peter Andersen, Djahida Bedja, Nuria Amat-Alarcon, Deeptankar DeMazumder, Ravirasmi Jasti, Calum A. MacRae, Remo Leber, Andre G. Kleber, Jeffrey E. Saffitz, Daniel P. Judge
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Research Article Cardiology Genetics

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 exercised Dsg2mut/mut mice compared with Veh-treated Dsg2mut/mut mice 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

Stephen P. Chelko, Angeliki Asimaki, Peter Andersen, Djahida Bedja, Nuria Amat-Alarcon, Deeptankar DeMazumder, Ravirasmi Jasti, Calum A. MacRae, Remo Leber, Andre G. Kleber, Jeffrey E. Saffitz, Daniel P. Judge

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Figure 4

SB216763 treatment improves myocardial injury and cardiac function in JUP2157del2 and Dsg2mut/mut mice.

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SB216763 treatment improves myocardial injury and cardiac function in JU...
(A) Representative images of ventricular myocardia from JUP2157del2 and Dsg2mut/mut mice treated with vehicle (Veh) or SB216763 (SB2). Myocardia were immunostained with H&E, Masson’s trichrome (MTC), and TUNEL. Scale bar: 50 μm. Images are representative of n ≥ 4/genotype (white arrows, TUNEL-positive nuclei). (B) Percentage fibrosis and TUNEL-positive nuclei in hearts from SB2- and Veh-treated mutant mice. Fibrosis: n = 4/genotype; TUNEL: n = 4 for WT and Dsg2mut/mut mice and n = 6 for WT and JUP2157del2 mice. Mean ± SEM. P < 0.05 for WT vs. ACM mice using 2-tailed paired t test. (C) Quantitative ECG telemetry analysis of SB2-treated JUP2157del2 mice exhibited decreased bouts of single and >2 premature ventricular complexes. Representative ECG telemetry tracing from a vehicle-treated JUP2157del2 mouse. Mean ± SEM. P < 0.05 for SB2-treated JUP2157del2 (n = 16) vs. Veh-treated JUP2157del2 (n = 6) mice using 2-tailed t test with equal variance. (D) Echocardiography and ECG telemetry analysis of Veh- and SB2-treated Dsg2mut/mut mice. In box-and-whisker plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate 10th and 90th percentiles. Mean ± SEM, n = 4/genotype/treatment. *P < 0.05 for SB2-treated Dsg2mut/mut vs. Veh-treated Dsg2mut/mut mice using 2-way ANOVA with Tukey’s post-hoc analysis.