Research output: Contribution to journal › Article › peer-review
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; Vasichkina, Elena; Karpushev, Alexey; Tomilin, Alexey; Malashicheva, Anna; Kostareva, Anna.
In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1866, No. 11, 165915, 01.11.2020.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - 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
AU - Khudiakov, Aleksandr
AU - Zaytseva, Anastasia
AU - Perepelina, Kseniya
AU - Smolina, Natalia
AU - Pervunina, Tatiana
AU - Vasichkina, Elena
AU - Karpushev, Alexey
AU - Tomilin, Alexey
AU - Malashicheva, Anna
AU - Kostareva, Anna
N1 - Funding Information: This work was supported by Russian Science Foundation grants number 14-15-00745-П (iPSC-CMs signaling and electrophysiological experiments) and number 19-75-00070 (GSK3B experiments). Publisher Copyright: © 2020 Elsevier B.V. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Background: Mutations in desmosomal genes linked to arrhythmogenic cardiomyopathy are commonly associated with Wnt/β-catenin signaling abnormalities and reduction of the sodium current density. Inhibitors of GSK3B were reported to restore sodium current and improve heart function in various arrhythmogenic cardiomyopathy models, but mechanisms underlying this effect remain unclear. We hypothesized that there is a crosstalk between desmosomal proteins, signaling pathways, and cardiac sodium channels. Methods and results: To reveal molecular mechanisms of arrhythmogenic cardiomyopathy, we established human iPSC-based model of this pathology. iPSC-derived cardiomyocytes from patient carrying two genetic variants in PKP2 gene demonstrated that PKP2 haploinsufficiency due to frameshift variant, in combination with the missense variant expressed from the second allele, was associated with decreased Wnt/β-catenin activity and reduced sodium current. Different approaches were tested to restore impaired cardiomyocytes functions, including wild type PKP2 transduction, GSK3B inhibition and Wnt/β-catenin signaling modulation. Inhibition of GSK3B led to the restoration of both Wnt/β-catenin signaling activity and sodium current density in patient-specific cardiomyocytes while GSK3B activation led to the reduction of sodium current density. Moreover, we found that upon inhibition GSK3B sodium current was restored through Wnt/β-catenin-independent mechanism. Conclusion: We propose that alterations in GSK3B-Wnt/β-catenin signaling pathways lead to regulation of sodium current implying its role in molecular pathogenesis of arrhythmogenic cardiomyopathy.
AB - Background: Mutations in desmosomal genes linked to arrhythmogenic cardiomyopathy are commonly associated with Wnt/β-catenin signaling abnormalities and reduction of the sodium current density. Inhibitors of GSK3B were reported to restore sodium current and improve heart function in various arrhythmogenic cardiomyopathy models, but mechanisms underlying this effect remain unclear. We hypothesized that there is a crosstalk between desmosomal proteins, signaling pathways, and cardiac sodium channels. Methods and results: To reveal molecular mechanisms of arrhythmogenic cardiomyopathy, we established human iPSC-based model of this pathology. iPSC-derived cardiomyocytes from patient carrying two genetic variants in PKP2 gene demonstrated that PKP2 haploinsufficiency due to frameshift variant, in combination with the missense variant expressed from the second allele, was associated with decreased Wnt/β-catenin activity and reduced sodium current. Different approaches were tested to restore impaired cardiomyocytes functions, including wild type PKP2 transduction, GSK3B inhibition and Wnt/β-catenin signaling modulation. Inhibition of GSK3B led to the restoration of both Wnt/β-catenin signaling activity and sodium current density in patient-specific cardiomyocytes while GSK3B activation led to the reduction of sodium current density. Moreover, we found that upon inhibition GSK3B sodium current was restored through Wnt/β-catenin-independent mechanism. Conclusion: We propose that alterations in GSK3B-Wnt/β-catenin signaling pathways lead to regulation of sodium current implying its role in molecular pathogenesis of arrhythmogenic cardiomyopathy.
KW - Arrhythmogenic cardiomyopathy
KW - Glycogen synthase kinase 3 beta
KW - Plakophilin 2
KW - Sodium current
KW - Wnt/β-catenin signaling
KW - Mutation/genetics
KW - Humans
KW - Electrophysiology
KW - Sodium/metabolism
KW - Wnt Signaling Pathway/genetics
KW - Plakophilins/genetics
KW - Patch-Clamp Techniques
KW - Glycogen Synthase Kinase 3 beta/genetics
KW - HEK293 Cells
KW - Induced Pluripotent Stem Cells/metabolism
KW - Cardiomyopathies/genetics
KW - CELLS
KW - GLYCOGEN-SYNTHASE KINASE-3
KW - Wnt/beta-catenin signaling
KW - DIFFERENTIATION
KW - INHIBITORS
KW - MUTATIONS
KW - RIGHT-VENTRICULAR CARDIOMYOPATHY
UR - http://www.scopus.com/inward/record.url?scp=85089352325&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2020.165915
DO - 10.1016/j.bbadis.2020.165915
M3 - Article
C2 - 32768677
AN - SCOPUS:85089352325
VL - 1866
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 11
M1 - 165915
ER -
ID: 71709481