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Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
Jason D. Roberts, … , Melvin M. Scheinman, Peter J. Mohler
Jason D. Roberts, … , Melvin M. Scheinman, Peter J. Mohler
Published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3171-3184. https://doi.org/10.1172/JCI125538.
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Research Article Cardiology Cell biology

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

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Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Authors

Jason D. Roberts, Nathaniel P. Murphy, Robert M. Hamilton, Ellen R. Lubbers, Cynthia A. James, Crystal F. Kline, Michael H. Gollob, Andrew D. Krahn, Amy C. Sturm, Hassan Musa, Mona El-Refaey, Sara Koenig, Meriam Åström Aneq, Edgar T. Hoorntje, Sharon L. Graw, Robert W. Davies, Muhammad Arshad Rafiq, Tamara T. Koopmann, Shabana Aafaqi, Meena Fatah, David A. Chiasson, Matthew R.G. Taylor, Samantha L. Simmons, Mei Han, Chantal J.M. van Opbergen, Loren E. Wold, Gianfranco Sinagra, Kirti Mittal, Crystal Tichnell, Brittney Murray, Alberto Codima, Babak Nazer, Duy T. Nguyen, Frank I. Marcus, Nara Sobriera, Elisabeth M. Lodder, Maarten P. van den Berg, Danna A. Spears, John F. Robinson, Philip C. Ursell, Anna K. Green, Allan C. Skanes, Anthony S. Tang, Martin J. Gardner, Robert A. Hegele, Toon A.B. van Veen, Arthur A.M. Wilde, Jeff S. Healey, Paul M.L. Janssen, Luisa Mestroni, J. Peter van Tintelen, Hugh Calkins, Daniel P. Judge, Thomas J. Hund, Melvin M. Scheinman, Peter J. Mohler

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Figure 6

GSK3-β inhibition is sufficient to prevent cardiac remodeling associated with cardiac deletion of AnkB.

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GSK3-β inhibition is sufficient to prevent cardiac remodeling associated...
(A) Diagrammatic representation of GSK3-βi prevention study in Ank2fl/fl and Ank2-cKO mice. Echocardiograms were performed at the time points indicated by arrows. (B) Heart weight/tibia length ratios. n = 3. (C) Levels of p–β-catenin by IB of Ank2-cKO cardiac tissue lysates. n = 3. (D and E) Ejection fraction and fractional shortening at baseline. Ejection fraction (F) and fractional shortening (G) after 8 weeks of drug therapy in vehicle- and GSK3-βi–treated Ank2fl/fl and Ank2-cKO mice in the prevention study. n = 5 (D and E) and n = 9 (F and G). (H) Representative Masson’s trichrome–stained heart sections from vehicle-treated Ank2fl/fl mice. (I) Ank2fl/fl GSK-βi–treated, (J) Ank2-cKO vehicle-treated, and (K) Ank2-cKO GSK3-βi–treated mice after 8 weeks of drug therapy in the prevention study. Scale bars: 25 μm (I–K). Images are representative of 2 hearts from mice of each genotype and treatment condition. Data represent the mean ± SEM. Statistical analysis for C was done with a 2-tailed parametric t test at 95% CI. Statistical analysis for B and D–G was performed with a 2-way ANOVA followed by Tukey’s post hoc test.
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