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

Authors

AĆIMOVIĆ Ivana REFAAT Marwan M. MOREAU Adrien SALYKIN Anton REIKEN Steve SLEIMAN Yvonne SOUIDI Monia PŘIBYL Jan KAJAVA Andrey V. RICHARD Sylvian LU Jonathan T. CHEVALIER Philippe SKLÁDAL Petr DVOŘÁK Petr ROTREKL Vladimír MARKS Andrew R. SCHEINMAN Melvin M. LACAMPAGNE Alain MELI Albano C.

Year of publication 2018
Type Article in Periodical
Magazine / Source JOURNAL OF CLINICAL MEDICINE
MU Faculty or unit

Faculty of Medicine

Citation
Doi http://dx.doi.org/10.3390/jcm7110423
Keywords ryanodine receptor; CPVT; hiPSC-derived cardiomyocytes; calcium; beta-adrenergic receptor blockade; flecainide; post-translational modifications
Description 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.
Related projects:

You are running an old browser version. We recommend updating your browser to its latest version.

More info