Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency
Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency
复制标题
DOI：
10.1093/cvr/cvs218
复制
发表时间：
2012-09-01
影响因子：
10.8
通讯作者：
Delmar, Mario
中科院分区：
文献类型：
--
作者：
Cerrone, Marina;Noorman, Maartje;Delmar, Mario
ShRNA介导的桥粒蛋白PLAK-2的表达缺失导致钠电流(I-Na)功能障碍。目前尚不清楚PKP2基因单倍体缺陷是否会导致体内I-Na缺陷。在致心律失常的右室心肌病(ARVC)中检测到PKP2的突变。室颤和猝死通常发生在疾病的隐匿期，在显性结构损害之前。导致这些心律失常的机制仍然知之甚少。本研究旨在研究PKP2杂合子缺失(PKP2-HZ)小鼠心脏的形态、组织学和超微结构特征，并探讨PKP2丰度、I-Na功能和心脏电同步性之间的关系。与野生型(WT)相比，我们观察到PKP2-HZ心脏的超微结构，但没有组织学或大体解剖学上的差异。然而，在心肌细胞中，观察到i-Na的幅度降低，门控和动力学发生变化。为了进一步揭示I-Na缺乏症，我们将心肌细胞、兰登多夫灌流的心脏和麻醉动物暴露于药物挑战(氟卡胺)。在PKP2-HZ心脏中，氟卡胺引起的I-Na阻滞、心室传导受损和心电参数改变的程度比对照组更大。氟卡胺可引起PKP2-HZ动物的室性心律失常和死亡，但对小鼠无此作用。PKP2单倍体功能不全导致小鼠心脏I-Na缺乏。我们的数据支持桥粒和钠通道复合体之间存在串扰的概念。他们还表明，在PKP2缺乏的心脏中，I-Na功能障碍可能有助于心律失常的产生和/或维持。药理学挑战是否有助于揭示PKP2突变或变异患者的心律失常风险仍不确定。
The shRNA-mediated loss of expression of the desmosomal protein plakophilin-2 leads to sodium current (I-Na) dysfunction. Whether pkp2 gene haploinsufficiency leads to I-Na deficit in vivo remains undefined. Mutations in pkp2 are detected in arrhythmogenic right ventricular cardiomyopathy (ARVC). Ventricular fibrillation and sudden death often occur in the oconcealed phase' of the disease, prior to overt structural damage. The mechanisms responsible for these arrhythmias remain poorly understood. We sought to characterize the morphology, histology, and ultrastructural features of PKP2-heterozygous-null (PKP2-Hz) murine hearts and explore the relation between PKP2 abundance, I-Na function, and cardiac electrical synchrony.Hearts of PKP2-Hz mice were characterized by multiple methods. We observed ultrastructural but not histological or gross anatomical differences in PKP2-Hz hearts compared with wild-type (WT) littermates. Yet, in myocytes, decreased amplitude and a shift in gating and kinetics of I-Na were observed. To further unmask I-Na deficiency, we exposed myocytes, Langendorff-perfused hearts, and anaesthetized animals to a pharmacological challenge (flecainide). In PKP2-Hz hearts, the extent of flecainide-induced I-Na block, impaired ventricular conduction, and altered electrocardiographic parameters were larger than controls. Flecainide provoked ventricular arrhythmias and death in PKP2-Hz animals, but not in the WT.PKP2 haploinsufficiency leads to I-Na deficit in murine hearts. Our data support the notion of a cross-talk between desmosome and sodium channel complex. They also suggest that I-Na dysfunction may contribute to generation and/or maintenance of arrhythmias in PKP2-deficient hearts. Whether pharmacological challenges could help unveil arrhythmia risk in patients with mutations or variants in PKP2 remains undefined.