Sodium current abnormalities and deregulation of Wnt/β-catenin signaling in iPSC-derived cardiomyocytes generated from patient with arrhythmogenic cardiomyopathy harboring compound genetic variants in plakophilin 2 gene

Khudiakov, Aleksandr; Zaytseva, Anastasia; Perepelina, Kseniya; Smolina, Natalia; Pervunina, Tatiana; Васичкина, Е. С.; Karpushev, Alexey V.; Tomilin, Alexey; Malashicheva, Anna; Kostareva, Anna

doi:10.1016/j.bbadis.2020.165915

Cited by 21 publications

(19 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior studies of ARVC hiPSC-CMs have reported a range of electrophysiological characteristics. An hiPSC-CM model harboring a compound pathogenic variant in PKP2 showed abnormal sodium channel function as indicated by slowed upstroke speeds and reduced total sodium current [ 24 ]. A study of DSG2 p.G638R hiPSC-CMs found similar defects, and another study evaluating hiPSC-CMs derived from a patient with a rare homozygous DSG2 mutation (p.R119X) found very slow conduction velocities compared to an isogenic line with one wildtype DSG2 allele [ 25 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…These models have also revealed a number of electrical defects. PKP2-mutant hiPSC-CM models display altered calcium homeostasis and connexin-43 function [ 17 ] while both PKP2- and DSG2 -mutant hiPSC-CM models demonstrated slower action potential upstrokes and reduced sodium current density [ 24 , 25 ]. Inflammatory infiltration by immune cells has been shown to play an important role in pathologic remodeling of the myocardium in ARVC, and recent studies have indicated that ARVC hiPSC-CMs produce and secrete inflammatory cytokines via innate activation of nuclear factor-κB (NFκB) [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Altered Electrical, Biomolecular, and Immunologic Phenotypes in a Novel Patient-Derived Stem Cell Model of Desmoglein-2 Mutant ARVC

Hawthorne

Blazeski

Lowenthal

et al. 2021

JCM

View full text Add to dashboard Cite

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive heart condition which causes fibro-fatty myocardial scarring, ventricular arrhythmias, and sudden cardiac death. Most cases of ARVC can be linked to pathogenic mutations in the cardiac desmosome, but the pathophysiology is not well understood, particularly in early phases when arrhythmias can develop prior to structural changes. Here, we created a novel human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of ARVC from a patient with a c.2358delA variant in desmoglein-2 (DSG2). These DSG2-mutant (DSG2Mut) hiPSC-CMs were compared against two wildtype hiPSC-CM lines via immunostaining, RT-qPCR, Western blot, RNA-Seq, cytokine expression and optical mapping. Mutant cells expressed reduced DSG2 mRNA and had altered localization of desmoglein-2 protein alongside thinner, more disorganized myofibrils. No major changes in other desmosomal proteins were noted. There was increased pro-inflammatory cytokine expression that may be linked to canonical and non-canonical NFκB signaling. Action potentials in DSG2Mut CMs were shorter with increased upstroke heterogeneity, while time-to-peak calcium and calcium decay rate were reduced. These were accompanied by changes in ion channel and calcium handling gene expression. Lastly, suppressing DSG2 in control lines via siRNA allowed partial recapitulation of electrical anomalies noted in DSG2Mut cells. In conclusion, the aberrant cytoskeletal organization, cytokine expression, and electrophysiology found DSG2Mut hiPSC-CMs could underlie early mechanisms of disease manifestation in ARVC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Altered Electrical, Biomolecular, and Immunologic Phenotypes in a Novel Patient-Derived Stem Cell Model of Desmoglein-2 Mutant ARVC

Hawthorne

Blazeski

Lowenthal

et al. 2021

JCM

View full text Add to dashboard Cite

show abstract

“…Besides β-catenin, PG also participates in Wnt signaling by competing with β-catenin for degradation and transcriptional activation of TCF/LEF ( Huber and Petersen, 2015 ; Aktary et al, 2017 ). Moreover, several other desmosomal proteins, e.g., DSG2, DSC3, PKP1-3, and DSP directly or indirectly affected Wnt signaling ( Hardman et al, 2005 ; Yang et al, 2012 ; Miyazaki et al, 2016 ; Calore et al, 2019 ; Khudiakov et al, 2020 ; Hong et al, 2021 ). Wnt pathway components have been described to modulate stability, localization and/or function of desmosomal proteins.…”

Section: Regulation Of Desmosomal Functionsmentioning

confidence: 99%

Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

Müller

Hatzfeld

Keil

2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.

show abstract

“…Recent studies by Mohler and colleagues identified rare variants in ankyrin B in patients harboring desmosomal disease, ARVC, as well as a molecular link to the cardiac cell-cell junction via beta-catenin as targeted inhibition of the Wnt/beta-catenin pathways (SB-216763) could prevent and partially rescue ARVC phenotypes in cardiac-specific ankyrin B ( Ank2 )-deficient mice, revealing arrhythmogenic pathways in mice distinct from classic desmosomal structural alterations and remodeling (Roberts et al 2019 ). Independent studies utilizing human PKP2 mutant iPSC-derived cardiomyocytes further highlighted a role for Wnt/beta-catenin pathway in regulating sodium channel activity (Khudiakov et al 2020 ). Downregulation of Wnt/beta-Catenin signaling activity, and a corresponding reduction in sodium current density was observed in PKP2 mutant iPSC-derived cardiomyocytes, despite normal levels and localization of Nav1.5 (Khudiakov et al 2020 ).…”

Section: Arrhythmia Mechanisms Linking Cardiac Desmosome To Channel Functionmentioning

confidence: 99%

“…Independent studies utilizing human PKP2 mutant iPSC-derived cardiomyocytes further highlighted a role for Wnt/beta-catenin pathway in regulating sodium channel activity (Khudiakov et al 2020 ). Downregulation of Wnt/beta-Catenin signaling activity, and a corresponding reduction in sodium current density was observed in PKP2 mutant iPSC-derived cardiomyocytes, despite normal levels and localization of Nav1.5 (Khudiakov et al 2020 ). Restoration of Wnt/beta-Catenin signaling (SB-216763) can alleviate sodium current defects, implying that this pathway may be an important modulator of Nav1.5 activity (Fig.…”

Section: Arrhythmia Mechanisms Linking Cardiac Desmosome To Channel Functionmentioning

confidence: 99%

Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease

et al. 2021

View full text Add to dashboard Cite

Desmosomes are critical adhesion structures in cardiomyocytes, with mutation/loss linked to the heritable cardiac disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Early studies revealed the ability of desmosomal protein loss to trigger ARVC disease features including structural remodeling, arrhythmias, and inflammation; however, the precise mechanisms contributing to diverse disease presentations are not fully understood. Recent mechanistic studies demonstrated the protein degradation component CSN6 is a resident cardiac desmosomal protein which selectively restricts cardiomyocyte desmosomal degradation and disease. This suggests defects in protein degradation can trigger the structural remodeling underlying ARVC. Additionally, a subset of ARVC-related mutations show enhanced vulnerability to calpain-mediated degradation, further supporting the relevance of these mechanisms in disease. Desmosomal gene mutations/loss has been shown to impact arrhythmogenic pathways in the absence of structural disease within ARVC patients and model systems. Studies have shown the involvement of connexins, calcium handling machinery, and sodium channels as early drivers of arrhythmias, suggesting these may be distinct pathways regulating electrical function from the desmosome. Emerging evidence has suggested inflammation may be an early mechanism in disease pathogenesis, as clinical reports have shown an overlap between myocarditis and ARVC. Recent studies focus on the association between desmosomal mutations/loss and inflammatory processes including autoantibodies and signaling pathways as a way to understand the involvement of inflammation in ARVC pathogenesis. A specific focus will be to dissect ongoing fields of investigation to highlight diverse pathogenic pathways associated with desmosomal mutations/loss.

show abstract

Sodium current abnormalities and deregulation of Wnt/β-catenin signaling in iPSC-derived cardiomyocytes generated from patient with arrhythmogenic cardiomyopathy harboring compound genetic variants in plakophilin 2 gene

Cited by 21 publications

References 38 publications

Altered Electrical, Biomolecular, and Immunologic Phenotypes in a Novel Patient-Derived Stem Cell Model of Desmoglein-2 Mutant ARVC

Altered Electrical, Biomolecular, and Immunologic Phenotypes in a Novel Patient-Derived Stem Cell Model of Desmoglein-2 Mutant ARVC

Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease

Contact Info

Product

Resources

About