期刊
EMBO MOLECULAR MEDICINE
卷 4, 期 3, 页码 180-191出版社
WILEY
DOI: 10.1002/emmm.201100194
关键词
CPVT; dantrolene; disease modelling; induced pluripotent stem cells; ryanodine receptor 2
资金
- European Research Council (Marie Curie Excellence Team) [MEXT-23208, ERC 261053-CHD-iPS]
- German Research Foundation (Research Unit 923) [Mo 2217/1-1, La 1238 3-1/4-1]
- German Ministry for Education and Research [01 GN 0826]
- National Research Fund, Luxembourg [AFR-PHD-09-169]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据