title: Loss of cadherin-binding proteins β-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis.
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 (JUP). We previously reported that cardiac tissue-specific plakoglobin (PG) knockout (PG CKO) mice have no apparent conduction abnormality and survive longer than expected. Importantly, the PG homolog, β-catenin (CTNNB1), 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 heart (i.e., double knockout [DKO]). The DKO mice exhibited cardiomyopathy, fibrous tissue replacement, and conduction abnormalities resulting in SCD. Loss of the cadherin linker proteins resulted in dissolution of the intercalated disc (ICD) structure. Moreover, Cx43-containing gap junction plaques were reduced at the ICD, consistent with the arrhythmogenicity of the DKO hearts. Finally, ambulatory electrocardiogram monitoring captured the abrupt onset of spontaneous lethal ventricular arrhythmia in the DKO mice. In conclusion, these studies demonstrate that the N-cadherin-binding partners, PG and β-catenin, are indispensable for maintaining mechanoelectrical coupling in the heart.
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: David
authors.initials: D
authors.lastname: Swope
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Jifen
authors.initials: J
authors.lastname: Li
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D015820:Cadherins / Q000378:metabolism*; D018031:Connexin 43 / Q000378:metabolism; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017353:Gene Deletion; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism; D051185:gamma Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins; D018031:Connexin 43; D051176:beta Catenin; D051185:gamma Catenin