The Role of Plakoglobin and β-catenin in Mechano-Electrical Coupling of the Heart

David Swope, Thomas Jefferson University

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 JUP (plakoglobin). However, the mechanisms underlying plakoglobin dysfunction involved in the pathogenesis of ARVC remain poorly understood. Plakoglobin (PG) is a component of both desmosomes and adherens junctions located at the intercalated disc (ICD) of cardiomyocytes, where it functions to link cadherins to the cytoskeleton. To investigate the role of plakoglobin in ARVC, we generated an inducible cardiac restricted knockout (CKO) of the PG gene in mice. PG CKO mice exhibited progressive loss of cardiac myocytes, extensive inflammatory infiltration, fibrous tissue replacement, and cardiac dysfunction similar to those of ARVC patients. Despite gap junction remodeling, 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 is required to maintain cardiac conduction in the absence of PG, we generated mice lacking both PG and β-catenin specifically in the adult heart (DKO). The DKO mice exhibited cardiomyopathy, fibrous tissue replacement, dissolution of the ICD and conduction abnormalities resulting in SCD. Moreover, Cx43-containing gap junction plaques were reduced at the ICD, consistent with the arrhythmogenicity of the DKO hearts. Taken together, these studies demonstrate that the N-cadherin-binding partners, PG and β-catenin, are indispensable for maintaining mechanoelectrical coupling in the heart. In an effort to examine the affect of PG reduction in all tissues we utilized a novel PG hypomorphic allele that resulted in postnatal lethality. Surprisingly, significant reduction of PG at the ICD did not cause ARVC-like pathology in the PG hypomorph mice. Despite an increase in β-catenin, no change in β-catenin/TCF reporter activity was observed in PG hypomorph embryos suggesting that excess β-catenin was not likely causing increased transcription of Wnt/β-catenin target genes. These data suggest novel function(s) for PG beyond the heart and define a critical threshold of PG expression that is necessary for postnatal survival.

Subject Area

Molecular biology|Developmental biology

Recommended Citation

Swope, David, "The Role of Plakoglobin and β-catenin in Mechano-Electrical Coupling of the Heart" (2012). ETD Collection for Thomas Jefferson University. AAI3540216.
https://jdc.jefferson.edu/dissertations/AAI3540216

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