Intercalated disc abnormalities, reduced Na+ current density, and conduction slowing in desmoglein-2 mutant mice prior to cardiomyopathic changes

作者：Stefania Rizzo, Elisabeth M. Lodder, Arie O. Verkerk, Rianne Wolswinkel, Leander Beekman, Kalliopi Pilichou, Cristina Basso, Carol Ann Remme, Gaetano Thiene, Connie R. Bezzina · 发表于：Cardiovascular Research · 年份：2012 · DOI：10.1093/cvr/cvs219 · 被引用次数：209 · 研究领域：Cardiovascular Effects of Exercise、Cardiac electrophysiology and arrhythmias、Cardiomyopathy and Myosin Studies

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSION: Intercellular space widening at the level of the intercalated disc (desmosomes/adherens junctions) and a concomitant reduction in AP up...