Suppression of canonical Wnt/ -catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy
Open accessAbstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins.The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism.We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC.We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/b-catenin signaling through Tcf/Lef1 transcription factors.The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets.We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state.Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC.We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC.These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.Nonstandard abbreviations used: ARVC, arrhythmogenic right ventricular dysplasia/cardiomyopathy; C/EBP-a, CCAAT enhancer-binding protein-a; CPTV, catecholaminergic polymorphic ventricular tachycardia; DP, desmoplakin; a-MHC, a-myosin heavy chain; PG, plakoglobin; PKP2, plakophilin 2; SCD, sudden cardiac death; Tcf/ Lef, T cell/lymphoid-enhancing binding.
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Suppression of canonical Wnt/β-catenin signaling leads to ACM, prominently through competition with nuclear localization of JUP, rather than through β-catenin degradation.
“In a landmark study by Garcia-Gras E et al. [77], these authors demonstrated that suppression of canonical Wnt/β-catenin signaling leads to ACM, prominently through competition with nuclear localization of JUP, rather than through β-catenin degradation [77,79,80].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [77]
Recent evidence implicates fibro-adipogenic progenitors and epicardial-derived cells as primary sources, and they typically show epicardial to endocardial migration.
“Recent evidence implicates fibro-adipogenic progenitors and epicardial-derived cells as primary sources, and they typically show an epicardial to endocardial migration [77,79,83,84].”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [77]
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- Authors
- Garcia-Gras, E.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-07-03
- Volume
- 116
- Issue
- 7
- Pages
- 2012-2021
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1483165
- OpenAlex
- W2138839726
- Cited by
- 623
- References
- 2
- Citations by year
- 2026: 21 · 2025: 38 · 2024: 23 · 2023: 30 · 2022: 32 · 2021: 39 · 2020: 31 · 2019: 27 · 2018: 34 · 2017: 37 · 2016: 36 · 2015: 34 · 2014: 26 · 2013: 27 · 2012: 36
- FWCI
- 19.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Greater Houston Community Foundation
- National Institutes of Health (5p50hl042267-04)
- National Heart, Lung, and Blood Institute (R01-HL68884, P50 HL 42267, R01HL088498, R01HL068884)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- arrhythmogenic right ventricular cardiomyopathy, desmoplakin, desmosomes, plakoglobin, Wnt/β-catenin signaling, myocardial fibrosis, adipogenesis, ventricular arrhythmias, cardiac morphogenesis, myocyte apoptosis, sudden cardiac death, catecholaminergic polymorphic ventricular tachycardia, disease models
- MeSH terms
- Animals, Cell Nucleus, Cells, Cultured, Electrophysiology, Embryo, Mammalian, Heart Atria, Humans, Phenotype, Signal Transduction, Mice, Knockout, Arrhythmogenic Right Ventricular Dysplasia, Myocytes, Cardiac, RNA, Small Interfering, Adipogenesis, Wnt Proteins, beta Catenin, Desmoplakins, gamma Catenin, Mice, TCF Transcription Factors
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