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Citations to this article

Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy
Stephen P. Chelko, … , Jeffrey E. Saffitz, Daniel P. Judge
Stephen P. Chelko, … , Jeffrey E. Saffitz, Daniel P. Judge
Published April 21, 2016
Citation Information: JCI Insight. 2016;1(5):e85923. https://doi.org/10.1172/jci.insight.85923.
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Research Article Cardiology Genetics Article has an altmetric score of 29

Central role for GSK3β in the pathogenesis of arrhythmogenic cardiomyopathy

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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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ET Hoorntje, A Posafalvi, P Syrris, KJ van der Velde, MC Bolling, A Protonotarios, LG Boven, N Amat-Codina, JA Groeneweg, AA Wilde, N Sobreira, H Calkins, RN Hauer, MF Jonkman, WJ McKenna, PM Elliott, RJ Sinke, MP van den Berg, SP Chelko, CA James, JP van Tintelen, DP Judge, JD Jongbloed, T Ai
PloS one 2018
Impact of Exercise Restriction on Arrhythmic Risk Among Patients With Arrhythmogenic Right Ventricular Cardiomyopathy
W Wang, G Orgeron, C Tichnell, B Murray, J Crosson, O Monfredi, J CadrinTourigny, H Tandri, H Calkins, CA James
Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease 2018
Potential new mechanisms of pro-arrhythmia in arrhythmogenic cardiomyopathy: focus on calcium sensitive pathways
CJ van Opbergen, M Delmar, TA van Veen
Netherlands Heart Journal 2017
WNT Signaling in Cardiac and Vascular Disease
S Foulquier, EP Daskalopoulos, G Lluri, KC Hermans, A Deb, WM Blankesteijn, MC Michel
Pharmacological reviews 2017
Molecular Mechanisms in the Pathogenesis of Arrhythmogenic Cardiomyopathy
JE Saffitz
Cardiovascular Pathology 2017
Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies
KO Brandão, VA Tabel, DE Atsma, CL Mummery, RP Davis
Disease models & mechanisms 2017
Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy
A Lorenzon, M Calore, G Poloni, LJ de Windt, P Braghetta, A Rampazzo
Oncotarget 2017
Neonatal Transplantation Confers Maturation of PSC-Derived Cardiomyocytes Conducive to Modeling Cardiomyopathy
GS Cho, DI Lee, E Tampakakis, S Murphy, P Andersen, H Uosaki, S Chelko, K Chakir, I Hong, K Seo, HS Chen, X Chen, C Basso, SR Houser, GF Tomaselli, B ORourke, DP Judge, DA Kass, C Kwon
Cell Reports 2017
Using Zebrafish for High-Throughput Screening of Novel Cardiovascular Drugs
A Kithcart, CA MacRae
JACC: Basic to Translational Science 2017
Risk Stratification in Arrhythmogenic Right Ventricular Cardiomyopathy
H Calkins, D Corrado, F Marcus
Circulation 2017
Genetics and Genomics of Single-Gene Cardiovascular Diseases
AJ Marian, E Rooij, R Roberts
Journal of the American College of Cardiology 2016

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