Molecular composition of the intercalated disc in a spontaneous canine animal model of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Oxford, Eva M.; Everitt, Melanie D.; Coombs, Wanda; Fox, Philip R.; Kraus, Marc S.; Gelzer, Anna R.; Saffitz, Jeffrey E.; Taffet, Steven M.; Moı̈se, N. Sydney; Delmar, Mario

doi:10.1016/j.hrthm.2007.05.025

Cited by 64 publications

(72 citation statements)

References 38 publications

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“…79 Inherited ARVC in boxer dogs is associated with the loss of gap junctions, suggesting that, as in humans, disruption of the molecular composition of the intercalated disc is a component of the disease. 80 However, the genetic causes of ARVC in dogs remain unknown, and efforts to identify mutations in desmosomal molecules have been futile. Alternatively, a number of investigators have turned to genetically modified mice as a model to study ARVC pathophysiology.…”

Section: Desmosomal Integrity and Junctional Complexes: Results From mentioning

confidence: 99%

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

Delmar

McKenna

2010

Circulation Research

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240

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Section: Desmosomal Integrity and Junctional Complexes: Results From mentioning

confidence: 99%

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

Delmar

McKenna

2010

Circulation Research

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271

240

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“…In arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), decreased Cx43 levels are found already in the early stages, whereas fibrosis becomes more abundant during the progression of the disease. 12,13 This suggests a possible role of reduced Cx43 expression levels in the deposition of collagen in vulnerable hearts. A supportive recent in vitro study 14 suggested increased proliferation of cardiac fibroblasts, the primary source of cells responsible for production of interstitial collagen, once the intercellular communication was inhibited.…”

Section: Clinical Perspective On P 390mentioning

confidence: 98%

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

Jansen

Veen

Jong

et al. 2012

Circ: Arrhythmia and Electrophysiology

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Background-Arrhythmogenic ventricular remodeling is hallmarked by both reduced gap junction expression and increased collagen deposition. We hypothesized that reduced connexin43 (Cx43) expression is responsible for enhanced fibrosis in the remodeled heart, resulting in an arrhythmogenic substrate. Therefore, we investigated the effect of normal or reduced Cx43 expression on the formation of fibrosis in a physiological (aging) and pathophysiological (transverse aortic constriction [TAC]) mouse model. Methods and Results-The Cx43fl/fl and Cx43 CreER(T)/fl mice were aged 18 to 21 months or, at the age of 3 months, either TAC or sham operated and euthanized after 16 weeks. Epicardial activation mapping of the right and left ventricles was performed on Langendorff perfused hearts. Sustained ventricular arrhythmias were induced in 0 of 11 aged Cx43 fl/fl and 10 of 15 Cx43Cre-ER(T)/fl mice (PϽ0.01). Cx43 expression was reduced by half in aged Cx43 CreER(T)/fl compared with aged Cx43 fl/fl mice, whereas collagen deposition was significantly increased from 1.1Ϯ0.2% to 7.4Ϯ1.3%. Aged Cx43CreER(T)/fl mice with arrhythmias had significantly higher levels of fibrosis and conduction heterogeneity than aged Cx43CreER(T)/fl mice without arrhythmias. The TAC operation significantly increased fibrosis in control compared with sham (4.0Ϯ1.2% versus 0.4Ϯ0.06%), but this increase was significantly higher in Cx43CreER(T)/fl mice (10.8Ϯ1.4%). Discoidin domain receptor 2 expression was unchanged, but procollagen peptide I and III expression and collagen type 1␣2 mRNA levels were higher in TAC-operated Cx43HZ mice. Conclusions-Reduced cellular coupling results in more excessive collagen deposition during aging or pressure overload in mice due to enhanced fibroblast activity, leading to increased conduction in homogeneity and proarrhythmia. (Circ Arrhythm Electrophysiol. 2012;5:380-390.)Key Words: arrhythmia Ⅲ collagen Ⅲ electrophysiology mapping Ⅲ connexin43 Ⅲ fibroblast I n the heart, the highly orchestrated propagation of the electric impulse balances on the delicate interplay between excitability, cell-to-cell coupling, and architecture of myocardial tissue. An important aspect of the myocardial architecture is interstitial collagen (fibrosis), which, together with connexin43 (Cx43), determines cell-to-cell coupling in ventricular myocardium. Under normal physiological conditions, the amount of collagen between the cardiomyocytes is low (Ͻ1% of total tissue volume) but contributes to the structural organization of the heart and the anisotropic character of impulse propagation. We recently showed that, in senescent mouse hearts, collagen content was increased (200%) and Cx43 expression was decreased (50%), changes that were associated with increased inducibility of ventricular tachycardias. 1 On the other hand, when the excessive deposition of fibrosis was prevented through long-term inhibition of the renin-angiotensin-aldosterone system, the normal pattern of Cx43 expression was preserved and arrhythmia vulnerability was strongly red...

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“…35 Because plakophilin-2 does not contain a PDZ domain, this suggests that Na v 1.5 could be differentially regulated by multiple proteins at the intercalated discs including SAP97 and plakophilin-2, similarly to the lateral membrane where it interacts with the DMC and ankyrin-G, within complexes that may or may not be distinct (Figure 8). Deciphering the specific and distinct roles of the different proteins in trafficking and/or anchoring of cardiac ion channels including Na v 1.5 to different cellular compartments will be the goal of future experiments.…”

Section: Physiological Relevance Of the Two Regulating Mechanismsmentioning

confidence: 99%

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

Petitprez

Zmoos

Ogrodnik³

et al. 2011

Circulation Research

245

237

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Rationale:The cardiac sodium channel Na v 1.5 plays a key role in excitability and conduction. The 3 last residues of Na v 1.5 (Ser-Ile-Val) constitute a PDZ-domain binding motif that interacts with the syntrophin-dystrophin complex. As dystrophin is absent at the intercalated discs, Na v 1.5 could potentially interact with other, yet unknown, proteins at this site.Objective: The aim of this study was to determine whether Na v 1.5 is part of distinct regulatory complexes at lateral membranes and intercalated discs. Methods and Results:Immunostaining experiments demonstrated that Na v 1.5 localizes at lateral membranes of cardiomyocytes with dystrophin and syntrophin. Optical measurements on isolated dystrophin-deficient mdx hearts revealed significantly reduced conduction velocity, accompanied by strong reduction of Na v 1.5 at lateral membranes of mdx cardiomyocytes. Pull-down experiments revealed that the MAGUK protein SAP97 also interacts with the SIV motif of Na v 1.5, an interaction specific for SAP97 as no pull-down could be detected with other cardiac MAGUK proteins (PSD95 or ZO-1). Furthermore, immunostainings showed that Na v 1.5 and SAP97 are both localized at intercalated discs. Silencing of SAP97 expression in HEK293 and rat cardiomyocytes resulted in reduced sodium current (I Na ) measured by patch-clamp. The I Na generated by Na v 1.5 channels lacking the SIV motif was also reduced. Finally, surface expression of Na v 1.5 was decreased in silenced cells, as well as in cells transfected with SIV-truncated channels. Conclusions:These data support a model with at least 2 coexisting pools of Na v 1.5 channels in cardiomyocytes: one targeted at lateral membranes by the syntrophin-dystrophin complex, and one at intercalated discs by SAP97. (Circ Res. 2011;108:294-304.) Key Words: sodium channel Ⅲ Na v 1.5 Ⅲ MAGUK proteins Ⅲ SAP97 Ⅲ dystrophin T he cardiac sodium channel Na v 1.5 initiates the cardiac action potential, thus playing a key role in cardiac excitability and impulse propagation. The physiological importance of this channel is illustrated by numerous cardiac pathologies caused by hundreds of mutations identified in SCN5A, the gene encoding Na v 1.5. 1 The Na v 1.5 channel is composed of one 220-kDa ␣-subunit that constitutes a functional channel, and 30-kDa ␤-subunits. In addition to these accessory ␤-subunits, several proteins have been shown to regulate and interact with Na v 1.5. 1,2 In most cases, the physiological relevance of these interactions is poorly understood, mainly because of a lack of appropriate animal models. Many of the interacting proteins bind to the C terminus of Na v 1.5, where several protein-protein interaction motifs are located. 1,2 We have shown that the ubiquitin-protein ligase Nedd4-2 binds the PY motif of Na v 1.5 and reduces the sodium current (I Na ) in HEK293 cells by promoting its internalization. 3 We have also demonstrated that Na v 1.5 associates with the dystrophin-syntrophin multiprotein complex (DMC) in cardiac cells. 4 In dystrophin-deficient mice (m...

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Molecular composition of the intercalated disc in a spontaneous canine animal model of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Cited by 64 publications

References 38 publications

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes

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Molecular composition of the intercalated disc in a spontaneous canine animal model of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Cited by 64 publications

References 38 publications

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

Reduced Cx43 Expression Triggers Increased Fibrosis Due to Enhanced Fibroblast Activity

SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na v 1.5 in Cardiomyocytes

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SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Na _v 1.5 in Cardiomyocytes