Dantrolene rescues arrhythmogenic RYR2 defect in a patient‐specific stem cell model of catecholaminergic polymorphic ventricular tachycardia

EMBO Molecular Medicine

Christian B. Jung⁴  Alessandra Moretti⁴  Michael Mederos y Schnitzler¹  Laura Iop⁴  Ursula Storch¹  Milena Bellin⁴  Tatjana Dorn⁴  Sandra Ruppenthal²  Sarah Pfeiffer¹  Alexander Goedel⁴  Ralf J. Dirschinger⁴  Melchior Seyfarth⁵  Jason T. Lam⁴  Daniel Sinnecker⁴  Thomas Gudermann³  Peter Lipp⁶ 

[1] Walther-Straub-Institut für Pharmakologie and Toxikologie, Ludwig-Maximilians Universität München, Goethetraße, München, Germany;Institut für Molekulare Zellbiologie, Medizinische Fakultät, Universitätsklinikum Homburg/Saar, Universität des Saarlandes, Homburg/Saar, Germany;E-mail address: E-mail address: 关键词: CPVT;    dantrolene;    disease modelling;    induced pluripotent stem cells;    ryanodine receptor 2;   

DOI  :  10.1002/emmm.201100194

来源: Wiley

【 摘 要 】

Abstract

Coordinated release of calcium (Ca²⁺) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca²⁺ release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca²⁺ concentrations, a reduced SR Ca²⁺ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca²⁺ release events (Ca²⁺ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca²⁺ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.

【 授权许可】

Unknown   
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