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

Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua 35121, Italy.
Cardiovascular Research (Impact Factor: 5.94). 07/2012; 95(4):409-18. DOI: 10.1093/cvr/cvs219
Source: PubMed


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.

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Available from: Arie O Verkerk, Jan 28, 2015
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    • "Several co-immunoprecipitation studies have shown that mechanical and electrical junctions and ion channel proteins interact amongst each other (Agullo-Pascual et al. 2013; Rizzo et al. 2012; Sato et al. 2009). The destruction of these interactions might contribute to abnormal tissue electrophysiology in the concealed phase of ACM, during which arrhythmias might occur in the absence of structural changes. "
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    ABSTRACT: Arrhythmogenic cardiomyopathy (ACM) is an acquired progressive disease having an age-related penetrance and showing clinical manifestations usually during adolescence and young adulthood. It is characterized clinically by a high incidence of severe ventricular tachyarrhythmias and sudden cardiac death and pathologically by degeneration of ventricular cardiomyocytes with replacement by fibro-fatty tissue. Whereas, in the past, the disease was considered to involve only the right ventricle, more recent clinical studies have established that the left ventricle is frequently involved. ACM is an inherited disease in up to 50 % of cases, with predominantly an autosomal dominant pattern of transmission, although recessive inheritance has also been described. Since most of the pathogenic mutations have been identified in genes encoding desmosomal proteins, ACM is currently defined as a disease of desmosomes. However, on the basis of the most recent description of the intercalated disc organization and of the identification of a novel ACM gene encoding for an area composita protein, ACM can be considered as a disease of the intercalated disc, rather than only as a desmosomal disease. Despite increasing knowledge of the genetic basis of ACM, we are just beginning to understand early molecular events leading to cardiomyocyte degeneration, fibrosis and fibro-fatty substitution. This review summarizes recent advances in our comprehension of the link between the molecular genetics and pathogenesis of ACM and of the novel role of cardiac intercalated discs.
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    • "Young age (low, high expressors): No reported effects on ICD Old age (low expressors): Premature ventricular beats, monomorphic and polymorphic ventricular tachycardia and atrial arrhythmias Ventricular conduction slowing and susceptibility to induced Pilichou et al. (2009), Rizzo et al. (2012) "
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    • "The N266S substitution alters the second calcium coordination site responsible for rigidification and cis-interactions of the extracellular domain. Mice that express the corresponding DSG2 mutation show separated junctions and widened intercellular spaces, suggesting defective adhesion, and developed macroscopic lesions and ARVC features including sudden death, spontaneous ventricular arrhythmias, and cardiac dysfunction [52] [56] [57]. The more dramatic deletion of the first Fig. 2. Desmosomal cadherin structures. "

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