Document Detail

Restrictive loss of plakoglobin in cardiomyocytes leads to arrhythmogenic cardiomyopathy.
MedLine Citation:
PMID:  21880664     Owner:  NLM     Status:  MEDLINE    
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inheritable myocardial disorder associated with fibrofatty replacement of myocardium and ventricular arrhythmia. A subset of ARVC is categorized as Naxos disease, which is characterized by ARVC and a cutaneous disorder. A homozygous loss-of-function mutation of the Plakoglobin (Jup) gene, which encodes a major component of the desmosome and the adherens junction, had been identified in Naxos patients, although the underlying mechanism remained elusive. We generated Jup mutant mice by ablating Jup in cardiomyocytes. Jup mutant mice largely recapitulated the clinical manifestation of human ARVC: ventricular dilation and aneurysm, cardiac fibrosis, cardiac dysfunction and spontaneous ventricular arrhythmias. Ultra-structural analyses revealed that desmosomes were absent in Jup mutant myocardia, whereas adherens junctions and gap junctions were preserved. We found that ventricular arrhythmias were associated with progressive cardiomyopathy and fibrosis in Jup mutant hearts. Massive cell death contributed to the cardiomyocyte dropout in Jup mutant hearts. Despite the increase of β-catenin at adherens junctions in Jup mutant cardiomyoicytes, the Wnt/β-catenin-mediated signaling was not altered. Transforming growth factor-beta-mediated signaling was found significantly elevated in Jup mutant cardiomyocytes at the early stage of cardiomyopathy, suggesting an important pathogenic pathway for Jup-related ARVC. These findings have provided further insights for the pathogenesis of ARVC and potential therapeutic interventions.
Deqiang Li; Ying Liu; Mitsunori Maruyama; Wuqiang Zhu; Hanying Chen; Wenjun Zhang; Sean Reuter; Shien-Fong Lin; Laura S Haneline; Loren J Field; Peng-Sheng Chen; Weinian Shou
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-31
Journal Detail:
Title:  Human molecular genetics     Volume:  20     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-08     Completed Date:  2012-02-22     Revised Date:  2013-07-30    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  4582-96     Citation Subset:  IM    
Riley Heart Research Center, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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MeSH Terms
Arrhythmias, Cardiac / complications,  physiopathology
Arrhythmogenic Right Ventricular Dysplasia / complications,  pathology*,  physiopathology
Cell Death
Desmosomes / metabolism,  ultrastructure
Gene Deletion
Heart Conduction System / pathology,  physiopathology
Mice, Mutant Strains
Myocardium / metabolism,  pathology
Myocytes, Cardiac / metabolism*,  pathology*,  ultrastructure
Organ Specificity
Sarcomeres / metabolism,  ultrastructure
Wnt Signaling Pathway
gamma Catenin / deficiency*,  metabolism
Grant Support
Reg. No./Substance:
0/gamma Catenin

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