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Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes

Authors :
Petr Skládal
Marwan M. Refaat
Alain Lacampagne
Anton Salykin
Jan Přibyl
Melvin M. Scheinman
Andrew R. Marks
Vladimír Rotrekl
Adrien Moreau
Albano C. Meli
Philippe Chevalier
Sylvain Richard
Yvonne Sleiman
Andrey V. Kajava
Jonathan T. Lu
Steve Reiken
Monia Souidi
Petr Dvořák
Ivana Acimovic
Masaryk University
American University of Beirut [Beyrouth] (AUB)
Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Université Claude Bernard Lyon 1 (UCBL)
Université de Lyon
St. Anne’s University Hospital [Brno]
Columbia University College of Physicians and Surgeons
Centre de recherche en Biologie Cellulaire (CRBM)
Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
University of California [San Francisco] (UCSF)
University of California
MORNET, Dominique
Masaryk University [Brno] (MUNI)
Centre de recherche en Biologie cellulaire de Montpellier (CRBM)
Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
University of California [San Francisco] (UC San Francisco)
University of California (UC)
Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Masaryk University and University Hospital Brno
American University of Beirut Faculty of Medicine and Medical Center
Physiologie des plantes et des champignons lors de l'infection
Bayer Cropscience-Centre National de la Recherche Scientifique (CNRS)
Division de Rythmologie
Hospices Civils de Lyon (HCL)
Department of biochemistry, Masaryk University
Faculty of Medicine
Columbia University [New York]
Source :
Journal of Clinical Medicine Research, Journal of Clinical Medicine Research, Elmer Press, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine Research, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Journal of Clinical Medicine, MDPI, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Vol 7, Iss 11, p 423 (2018), Journal of clinical medicine, vol 7, iss 11, Journal of Clinical Medicine; Volume 7; Issue 11; Pages: 423
Publication Year :
2018
Publisher :
HAL CCSD, 2018.

Abstract

Background: Sarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. Objective: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. Methods: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. Results: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. Conclusion: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband’s resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms.

Details

Language :
English
ISSN :
19183003, 19183011, and 20770383
Database :
OpenAIRE
Journal :
Journal of Clinical Medicine Research, Journal of Clinical Medicine Research, Elmer Press, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine Research, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Journal of Clinical Medicine, MDPI, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Vol 7, Iss 11, p 423 (2018), Journal of clinical medicine, vol 7, iss 11, Journal of Clinical Medicine; Volume 7; Issue 11; Pages: 423
Accession number :
edsair.doi.dedup.....2745d8a809abd3269f2570e77b1e9281
Full Text :
https://doi.org/10.3390/jcm7110423⟩