Intercalated disc abnormalities, reduced Na+ current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes
Intercalated disc abnormalities, reduced Na+ current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes
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DOI：
10.1093/cvr/cvs219
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发表时间：
2012-09-01
影响因子：
10.8
通讯作者：
Bezzina, Connie R.
中科院分区：
文献类型：
--
作者：
Rizzo, Stefania;Lodder, Elisabeth M.;Bezzina, Connie R.
编码桥粒蛋白的基因突变与致心律失常性右心室心肌病（ARVC）的发病机制有关。然而，这些突变在疾病早期阶段的后果是未知的。我们研究了突变诱导的闰盘重塑是否会影响细胞死亡和替代纤维化发生之前的电生理特性。在细胞死亡和替代纤维化发生之前和之后，研究了心脏过表达突变桥粒芯糖蛋白2（Dsg 2）Dsg 2-N271 S（Tg-NS/L）的转基因小鼠。心脏过表达野生型Dsg 2的小鼠和野生型小鼠作为对照。通过电子显微镜进行的评估确定，在坏死和纤维化发生之前，Tg-NS/L小鼠的桥粒/粘附连接处的细胞间隙变宽。在这个阶段，Langendorff灌注心脏的心外膜标测显示心室激动时间延长，纵向和横向传导速度降低，心律失常诱发率增加。在疾病的这个阶段，还观察到由于较低的Na电流密度导致的动作电位（AP）上升速度降低。此外，免疫共沉淀证实了Dsg 2和Na通道蛋白Na（V）1.5之间的体内相互作用。在坏死和替代性纤维化发生之前的疾病阶段，由于较低的Na电流密度，在闰盘水平（桥粒/粘附连接）的细胞间隙增宽和伴随的AP上行速度降低导致传导减慢和心律失常易感性增加。Dsg 2和Na（V）1.5之间的体内相互作用的证明为在早期ARVC阶段期间观察到的电干扰提供了分子途径。
Mutations in genes encoding desmosomal proteins have been implicated in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, the consequences of these mutations in early disease stages are unknown. We investigated whether mutation-induced intercalated disc remodelling impacts on electrophysiological properties before the onset of cell death and replacement fibrosis.Transgenic mice with cardiac overexpression of mutant Desmoglein2 (Dsg2) Dsg2-N271S (Tg-NS/L) were studied before and after the onset of cell death and replacement fibrosis. Mice with cardiac overexpression of wild-type Dsg2 and wild-type mice served as controls. Assessment by electron microscopy established that intercellular space widening at the desmosomes/adherens junctions occurred in Tg-NS/L mice before the onset of necrosis and fibrosis. At this stage, epicardial mapping in Langendorff-perfused hearts demonstrated prolonged ventricular activation time, reduced longitudinal and transversal conduction velocities, and increased arrhythmia inducibility. A reduced action potential (AP) upstroke velocity due to a lower Na current density was also observed at this stage of the disease. Furthermore, co-immunoprecipitation demonstrated an in vivo interaction between Dsg2 and the Na channel protein Na(V)1.5.Intercellular space widening at the level of the intercalated disc (desmosomes/adherens junctions) and a concomitant reduction in AP upstroke velocity as a consequence of lower Na current density lead to slowed conduction and increased arrhythmia susceptibility at disease stages preceding the onset of necrosis and replacement fibrosis. The demonstration of an in vivo interaction between Dsg2 and Na(V)1.5 provides a molecular pathway for the observed electrical disturbances during the early ARVC stages.