Viral Gene Transfer Rescues Arrhythmogenic Phenotype and Ultrastructural Abnormalities in Adult Calsequestrin-Null Mice With Inherited Arrhythmias
Viral Gene Transfer Rescues Arrhythmogenic Phenotype and Ultrastructural Abnormalities in Adult Calsequestrin-Null Mice With Inherited Arrhythmias
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DOI：
10.1161/circresaha.111.263939
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发表时间：
2012-03-02
影响因子：
20.1
通讯作者：
Priori, Silvia Giuliana
中科院分区：
文献类型：
--
作者：
Denegri, Marco;Avelino-Cruz, Jose Everardo;Priori, Silvia Giuliana
基本原理：儿茶酚胺能多形性室性心动过速是一种易导致心脏骤停和猝死的遗传性疾病。该疾病与编码心脏ryanodine受体（RyR 2）和心脏钙螯合蛋白（CASQ 2）的基因突变有关。CASQ 2突变导致CASQ 2单体的大量丢失，可能是因为突变蛋白的降解增强。CASQ 2的减少与Triadin（TrD）和Junctin（JnC）水平的降低有关，这两种蛋白与CASQ 2和RyR 2形成一种大分子复合物，专门用于控制肌浆网中钙的释放。目的：我们打算评估野生型CASQ 2的病毒基因转移是否可以挽救突变CASQ 2引起的广泛异常。我们使用腺相关血清9型病毒载体表达绿色荧光蛋白标记的CASQ 2构建体。在新生CASQ 2 KO小鼠中腹膜内注射载体20周后，我们观察到钙螯合蛋白、三联蛋白和连接蛋白水平的正常化，CASQ 2消融引起的电生理和超微结构异常的挽救，以及没有危及生命的心律失常。我们已经证明了在基因敲除小鼠中诱导CASQ 2表达的概念，和电异常，并预防CASQ 2缺陷型儿茶酚胺能多态性室性心动过速小鼠危及生命的心律失常。这些数据支持CASQ 2病毒基因转移的发展可能具有临床应用的观点。(Circ Res. 2012;110：663-668）。
Rationale: Catecholaminergic polymorphic ventricular tachycardia is an inherited disease that predisposes to cardiac arrest and sudden death. The disease is associated with mutations in the genes encoding for the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2). CASQ2 mutations lead to a major loss of CASQ2 monomers, possibly because of enhanced degradation of the mutant protein. The decrease of CASQ2 is associated with a reduction in the levels of Triadin (TrD) and Junctin (JnC), two proteins that form, with CASQ2 and RyR2, a macromolecular complex devoted to control of calcium release from the sarcoplasmic reticulum.Objective: We intended to evaluate whether viral gene transfer of wild-type CASQ2 may rescue the broad spectrum of abnormalities caused by mutant CASQ2.Methods and Results: We used an adeno-associated serotype 9 viral vector to express a green fluorescent protein-tagged CASQ2 construct. Twenty weeks after intraperitoneal injection of the vector in neonate CASQ2 KO mice, we observed normalization of the levels of calsequestrin, triadin, and junctin, rescue of electrophysiological and ultrastructural abnormalities caused by CASQ2 ablation, and lack of life-threatening arrhythmias.Conclusions: We have proven the concept that induction of CASQ2 expression in knockout mice reverts the molecular, structural, and electric abnormalities and prevents life-threatening arrhythmias in CASQ2-defective catecholaminergic polymorphic ventricular tachycardia mice. These data support the view that development of CASQ2 viral gene transfer could have clinical application. (Circ Res. 2012;110:663-668.)