Cardiomyocyte-targeted overexpression of the coxsackie–adenovirus receptor causes a cardiomyopathy in association with β-catenin signaling

Caruso, L; Yuen, Stella; Smith, Julie M; Husain, Mansoor; Opavsky, Mary Anne

doi:10.1016/j.yjmcc.2010.01.022

Cited by 30 publications

(32 citation statements)

References 53 publications

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“…Transmission electron microscopy however revealed morphological changes with less well-defined contacts between myocytes in the cKOs. These results are well in line with the suggested role of CAR in organization of cell-cell contacts and the crosstalk between CAR and connexin proteins in the heart [12], [13].…”

Section: Discussionsupporting

confidence: 89%

“…Moreover, a defective communication through tight- and gap junctions in cardiomyocytes has been suggested [12]. In contrast, cardiac-specific overexpression of CAR causes disorganization and degeneration of cardiomyocytes, disrupted adherens junctions, cardiomyopathy and ultimately animal death [13]. Overexpression of CAR driven by a skeletal muscle-specific promoter results in a severe and lethal myopathic phenotype [14].…”

Section: Introductionmentioning

confidence: 99%

“…CAR protein levels are dynamically regulated by inflammatory responses and signals that control proliferation and differentiation including the Raf/MEK/ERK, FSH and TGF-ß mediated signalling pathways [15], [16], [17], [18], [19], [20], [21], [22]. CAR has also been associated with an activation of both β-catenin- MAPK and PI3K signaling pathways [13], [23], [24].…”

Section: Introductionmentioning

confidence: 99%

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Multiple Phenotypes in Adult Mice following Inactivation of the Coxsackievirus and Adenovirus Receptor (Car) Gene

et al. 2011

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To determine the normal function of the Coxsackievirus and Adenovirus Receptor (CAR), a protein found in tight junctions and other intercellular complexes, we constructed a mouse line in which the CAR gene could be disrupted at any chosen time point in a broad spectrum of cell types and tissues. All knockouts examined displayed a dilated intestinal tract and atrophy of the exocrine pancreas with appearance of tubular complexes characteristic of acinar-to-ductal metaplasia. The mice also exhibited a complete atrio-ventricular block and abnormal thymopoiesis. These results demonstrate that CAR exerts important functions in the physiology of several organs in vivo.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiple Phenotypes in Adult Mice following Inactivation of the Coxsackievirus and Adenovirus Receptor (Car) Gene

et al. 2011

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“…Additionally, cardiac specific over-expression of adhesion proteins such as N-cadherin, E-cadherins or the Coxsackie-Adenovirus-receptor (CAR) also cause heart failure in mice [42, 43], suggesting that cardiomyocyte adhesion is sensitively controlled, dosage dependent, and needs fine-tuning and adjustments by different adhesion proteins.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling

et al. 2017

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BackgroundArrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.Methods and resultsWe generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.ConclusionCardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.

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“…Therefore, CAR might have a dual function in the pathogenesis of myocarditis: as viral receptor and in addition induction of signals that activate components characteristic of innate immunity. Interestingly, increased CAR expression in the adult heart caused a cardiac phenotype distinct from that observed following embryonic overexpression of CAR which resulted in disrupted cardiomyocyte junctions (Caruso et al 2010 ). An active role of CAR re-expression in diseased cardiac tissue is supported by a similar observation made in regenerating skeletal muscle.…”

Section: Car Re-expression In Diseased Cardiac and Skeletal Musclementioning

confidence: 99%

The IgCAMs CAR, BT-IgSF, and CLMP: Structure, Function, and Diseases

Schreiber

Langhorst

Jüttner

et al. 2013

Advances in Neurobiology

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The coxsackie-adenovirus receptor (CAR) is the prototype of a small subfamily of IgCAMs composed of CAR itself, CLMP, BT-IgSF, ESAM, CTX, and A33. These six proteins are composed of one V-set and one C2-set Ig domains and a single transmembrane helix followed by a cytoplasmic stretch. They are localized in several tissues and organs and -except for ESAM, CTX, and A33 -are expressed in the developing brain. CAR becomes downregulated at early postnatal stages and is absent from the adult brain. CAR, CLMP, and BT-IgSF mediate homotypic aggregation. Interestingly, cell adhesion experiments, binding studies, and crystallographic investigations on the extracellular domain reveal a fl exible ectodomain for CAR that mediates homophilic and heterophilic binding.CAR has been extensively investigated in the context of gene therapy and diseases, while research on BT-IgSF and CLMP is at an early stage. Several mouse models as well as studies on patient tissues revealed an essential role for CAR in (1) the development of cardiac, renal, lymphatic, and intestinal tissue; (2) muscle pathology, remodeling, and regeneration; (3) tumor genesis/suppression and metastatic progression; and (4) in virus-mediated infections and gene therapy. Although the in vivo function of CAR in the brain has not been solved its developmentally regulated expression pattern in the brain as well as its function as CAM suggests that CAR might be implicated in neuronal network formation.

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Cardiomyocyte-targeted overexpression of the coxsackie–adenovirus receptor causes a cardiomyopathy in association with β-catenin signaling

Cited by 30 publications

References 53 publications

Multiple Phenotypes in Adult Mice following Inactivation of the Coxsackievirus and Adenovirus Receptor (Car) Gene

Multiple Phenotypes in Adult Mice following Inactivation of the Coxsackievirus and Adenovirus Receptor (Car) Gene

Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling

The IgCAMs CAR, BT-IgSF, and CLMP: Structure, Function, and Diseases

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