Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia.
Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia.
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DOI：
10.1002/emmm.201100194
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发表时间：
2012-03
影响因子：
11.1
通讯作者：
Laugwitz, Karl-Ludwig
中科院分区：
文献类型：
--
作者：
Jung, Christian B.;Moretti, Alessandra;Mederos Y Schnitzler, Michael;Iop, Laura;Storch, Ursula;Bellin, Milena;Dorn, Tatjana;Ruppenthal, Sandra;Pfeiffer, Sarah;Goedel, Alexander;Dirschinger, Ralf J.;Seyfarth, Melchior;Lam, Jason T.;Sinnecker, Daniel;Gudermann, Thomas;Lipp, Peter;Laugwitz, Karl-Ludwig
通过心肌兰尼定受体(RYR2)通道从肌浆网(SR)协调释放钙(Ca~(2+))是心肌细胞功能所必需的。儿茶酚胺能多形性室性心动过速(CPVT)是一种遗传性疾病，其特征是心脏结构正常的年轻患者发生应激性室性心律失常，RYR2常染色体显性突变或Calequestrin隐性突变导致SR舒张期钙异常释放，导致去极化后延迟致心律失常(DADS)。在这里，我们报告了从一名携带新的RYR2 S406L突变的CPVT患者中产生诱导多能干细胞(IPSCs)。在患者IPSC来源的心肌细胞中，与对照心肌细胞相比，儿茶酚胺能应激导致舒张期钙离子浓度升高，肌浆网钙离子含量降低，并增加对DADS和心律失常的易感性。这是由于基本钙释放事件(钙火花)的频率和持续时间增加所致。丹曲林是一种治疗恶性高热的有效药物，它恢复了正常的钙离子触发特性，并挽救了导致心律失常的表型。这提示RYR2通道内有缺陷的结构域间相互作用是S406L突变的致病机制。我们的工作为研究人类心律失常的发病机制和开发治疗CPVT的新方法提供了一种新的体外模型。
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.
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影响因子：
4.8
作者：
Moretti, Alessandra;Bellin, Milena;Laugwitz, Karl-Ludwig
通讯作者：
Laugwitz, Karl-Ludwig
影响因子：
--
作者：
Gupta MK;Illich DJ;Gaarz A;Matzkies M;Nguemo F;Pfannkuche K;Liang H;Classen S;Reppel M;Schultze JL;Hescheler J;Sarić T
通讯作者：
Sarić T
影响因子：
64.5
作者：
Marx, SO;Reiken, S;Marks, AR
通讯作者：
Marks, AR
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.1
作者：
Paul-Pletzer, K;Yamamoto, T;Parness, J
通讯作者：
Parness, J