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Poster Session 2Session Title: Heart Failure Biology

Abstract P123: β- and γ-Catenin Cooperate to Maintain Mechanoelectrical Coupling in the Heart

David Swope, Lan Cheng, Jifen Li, Glenn Radice
Circulation Research. 2011;109:AP123
David Swope
Thomas Jefferson Univ, Philadelphia, PA
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Lan Cheng
Thomas Jefferson Univ, Philadelphia, PA
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Jifen Li
Thomas Jefferson Univ, Philadelphia, PA
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Glenn Radice
Thomas Jefferson Univ, Philadelphia, PA
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Abstract

Arrhythmic right ventricular cardiomyopathy (ARVC) is a hereditary heart-muscle disease that causes sudden cardiac death (SCD) in young people. Almost half of ARVC patients have a mutation in genes encoding cell adhesion proteins of the desmosome including plakoglobin (also known as γ-catenin). Plakoglobin (PG) is a unique cell adhesion molecule as it is located in both desmosomes and adherens junctions located at the intercalated disc (ID) where it functions to link cadherins to the cytoskeleton. Redistribution of PG away from ID is found in virtually all cases of ARVC, regardless of the specific mutation, suggesting that PG plays a fundamental role in the pathogenesis of ARVC. To investigate the role of PG in ARVC, we generated an inducible cardiac-restricted knockout (CKO) of the PG gene in mice. Despite gap junction remodelling, PG CKO mice have no apparent conduction abnormality and survive longer than expected. Importantly, the PG homolog, β-catenin, showed increased association with the gap junction protein, connexin43 (Cx43) in PG CKO hearts. To determine whether β-catenin protects PG mutant animals from sudden arrhythmic death, we generated mice lacking both PG and β-catenin specifically in the heart (i.e. double knockout, DKO). The PG/β-catenin DKO mice exhibited acute cardiomyopathy, fibrous tissue replacement, and conduction abnormalities resulting in SCD 3 – 5 months (124 day median survival) after deleting the genes. The PG/β-catenin DKO hearts were susceptible to induced arrhythmias (8/11 DKO versus 0/9 WT, p < 0.01) consistent with the SCD phenotype. Furthermore, spontaneous lethal arrhythmias were captured in PG/β-catenin DKO mice with telemetric monitoring. In contrast to the PG and β-catenin single mutants, N-cadherin was significantly reduced at the ID in the PG/β-catenin DKO mice. Consistent with decreased desmoglein-2 and plakophilin-2 at the ID, quantitative analysis of TEM images demonstrated a significant reduction in the number of desmosomes (7.36 ± 3.68 DKO versus 36.37 ± 4.44 WT per 100-µm ID; n = 10 fields per heart; p < 0.001). In conclusion, these studies suggest that increasing β-catenin interaction with Cx43 may enhance gap junction function in ARVC patients, thus improving electrical conduction in the heart.

  • Ventricular arrhythmia
  • Gap junctions
  • Cardiomyopathy
  • © 2011 by American Heart Association, Inc.
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Circulation Research
9 December 2011, Volume 109, Issue Suppl 1
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    Abstract P123: β- and γ-Catenin Cooperate to Maintain Mechanoelectrical Coupling in the Heart
    David Swope, Lan Cheng, Jifen Li and Glenn Radice
    Circulation Research. 2011;109:AP123, originally published October 8, 2015

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    Abstract P123: β- and γ-Catenin Cooperate to Maintain Mechanoelectrical Coupling in the Heart
    David Swope, Lan Cheng, Jifen Li and Glenn Radice
    Circulation Research. 2011;109:AP123, originally published October 8, 2015
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