Mechanisms of abnormal calcium homeostasis in mutations responsible for catecholaminergic polymorphic ventricular tachycardia
Mechanisms of abnormal calcium homeostasis in mutations responsible for catecholaminergic polymorphic ventricular tachycardia
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DOI：
10.1161/01.res.0000258468.31815.42
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发表时间：
2007-02-02
影响因子：
20.1
通讯作者：
Armoundas, Antonis A.
中科院分区：
文献类型：
--
作者：
Iyer, Vivek;Hajjar, Roger J.;Armoundas, Antonis A.
儿茶酚胺能多形性室性心动过速是一种因用力或压力而暴露的遗传性心律失常，其特征是触发性活动和心源性猝死。在这项研究中，我们模拟了与儿茶酚胺能多形性室性心动过速相关的 2 个基因的突变，第一个位于 calsequestrin (CSQN2)，第二个位于兰尼碱受体 (RyR2)。该研究的目的是调查导致受影响患者去极化延迟的自发 Ca2+ 释放事件的机制基础。将肌浆网 (SR) 腔内 Ca2+ 传感纳入人心室肌细胞模型中，并通过模拟破坏的 RyR2 腔内 Ca2+ 传感来模拟 CSQN2 突变。在电压钳模式下，突变型 CSQN2 模型重现了实验中观察到的更小的钙瞬变、更短的峰值钙瞬变时间以及加速的失活恢复。在电流钳模式下，在存在β刺激的情况下，我们观察到延迟的后去极化，这表明由受损的管腔Ca2+感应引起的RyR2的加速恢复是在表达突变CSQN2的肌细胞中观察到的触发活动的基础。在电流钳模式下，在以β刺激时FKBP12.6与RyR2结合减少为特征的突变体RyR2模型中，通过降低RyR2激活的协同性来模拟这些突变的受损耦合门控特征。在电流钳模式下，突变的 RyR2 模型表现出增加的舒张期 RyR2 打开概率，导致延迟后除极的形成。总之，突变体 CSQN2 和 RyR2 的这些最小阶模型提供了合理的机制，通过该机制，RyR2 门控缺陷可能导致心律失常的细胞触发，这对靶向治疗的开发具有影响。
Catecholaminergic polymorphic ventricular tachycardia is a heritable arrhythmia unmasked by exertion or stress and is characterized by triggered activity and sudden cardiac death. In this study, we simulated mutations in 2 genes linked to catecholaminergic polymorphic ventricular tachycardia, the first located in calsequestrin (CSQN2) and the second in the ryanodine receptor (RyR2). The aim of the study was to investigate the mechanistic basis for spontaneous Ca2+ release events that lead to delayed after depolarizations in affected patients. Sarcoplasmic reticulum (SR) luminal Ca2+ sensing was incorporated into a model of the human ventricular myocyte, and CSQN2 mutations were modeled by simulating disrupted RyR2 luminal Ca2+ sensing. In voltage-clamp mode, the mutant CSQN2 model recapitulated the smaller calcium transients, smaller time to peak calcium transient, and accelerated recovery from inactivation seen in experiments. In current clamp mode, in the presence of beta stimulation, we observed delayed afterdepolarizations, suggesting that accelerated recovery of RyR2 induced by impaired luminal Ca2+ sensing underlies the triggered activity observed in mutant CSQN2-expressing myocytes. In current-clamp mode, in a model of mutant RyR2 that is characterized by reduced FKBP12.6 binding to the RyR2 on beta stimulation, the impaired coupled gating characteristic of these mutations was modeled by reducing cooperativity of RyR2 activation. In current-clamp mode, the mutant RyR2 model exhibited increased diastolic RyR2 open probability that resulted in formation of delayed afterdepolarizations. In conclusion, these minimal order models of mutant CSQN2 and RyR2 provide plausible mechanisms by which defects in RyR2 gating may lead to the cellular triggers for arrhythmia, with implications for the development of targeted therapy.