Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy

Gard, Joseph J.; Yamada, Kiyomi; Green, Karen G.; Eloff, Benjamin C.; Rosenbaum, David S.; Wang, Xuejun; Robbins, Jeffrey; Schuessler, Richard B.; Yamada, Kathryn A.; Saffitz, Jeffrey E.

doi:10.1016/j.cardiores.2005.04.004

Cited by 49 publications

(38 citation statements)

References 29 publications

(56 reference statements)

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“…9B and C). Therefore, we conclude that HD mouse models develop an interstitial type fibrosis and are free from the fibrotic patches that can be observed in desmin-related cardiomyopathy [41], [42].…”

Section: Resultsmentioning

confidence: 63%

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

et al. 2014

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Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor.

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Section: Resultsmentioning

confidence: 63%

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

et al. 2014

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“…The altered cardiovascular physiology observed in desmin mutants is accompanied with conduction defects leading to abnormal ventricular contraction. Remodeling of gap junctions and mislocalization of Cx43 and other mechanical junction proteins like desmoplakin, plakoglobin, and N-cadherin were shown previously in a mouse model of desmin-related cardiomyopathy (Gard et al, 2005). Mislocalization of intercellular junction components is commonly observed in arrhythmogenic cardiomyopathies and triggers a loss of mechanical and electrical coupling of cardiomyocytes (Agullo-Pascual et al, 2014;Asimaki et al, 2014).…”

Section: Discussionmentioning

confidence: 91%

Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies

et al. 2015

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Desminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers. To date, the initial pathological steps of desminopathies and the impact of desmin aggregates in the genesis of the disease are unclear. Using live, high-resolution microscopy, we show that Desmin loss of function and Desmin aggregates promote skeletal muscle defects and alter heart biomechanics. In addition, we show that the calcium dynamics associated with heart contraction are impaired and are associated with sarcoplasmic reticulum dilatation as well as abnormal subcellular distribution of Ryanodine receptors. Our results demonstrate that desminopathies are associated with perturbed excitation-contraction coupling machinery and that aggregates are more detrimental than Desmin loss of function. Additionally, we show that pharmacological inhibition of aggregate formation and Desmin knockdown revert these phenotypes. Our data suggest alternative therapeutic approaches and further our understanding of the molecular determinants modulating Desmin aggregate formation.

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“…Abnormal ICD structure associated with downregulation of Ncadherin and Cx43 was observed in a hereditary hamster model of dilated cardiomyopathy (39,40). In a transgenic mouse model of human desmin-related cardiomyopathy, gap junction remodeling was accompanied by reduced N-cadherin at the ICD (41). In a guinea pig chronic pressure overload model, β-catenin was redistributed from the plasma membrane to the cytoplasm; however, there was no change in N-cadherin (42).…”

Section: Discussionmentioning

confidence: 99%

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

Levin

Xiong

et al. 2008

Journal of Molecular and Cellular Cardiology

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Cardiac-specific deletion of the murine gene (Cdh2) encoding the cell adhesion molecule, Ncadherin, results in disassembly of the intercalated disc (ICD) structure and sudden arrhythmic death. Connexin 43 (Cx43)-containing gap junctions are significantly reduced in the heart after depleting N-cadherin, therefore we hypothesized that animals expressing half the normal levels of N-cadherin would exhibit an intermediate phenotype. We examined the effect of N-cadherin haploinsufficiency on Cx43 expression and susceptibility to induced arrhythmias in mice either wild-type or heterozygous for the Cx43 (Gja1)-null allele. An increase in hypophosphorylated Cx43 accompanied by a modest decrease in total Cx43 protein levels was observed in the N-cadherin heterozygous mice. Consistent with these findings N-cadherin heterozygotes exhibited increased susceptibility to ventricular arrhythmias compared to wild-type mice. Quantitative immunofluorescence microscopy revealed a reduction in size of large Cx43-containing plaques in the N-cadherin heterozygous animals compared to wild-type. Gap junctions were further decreased in number and size in the N-cad/Cx43 compound heterozygous mice with increased arrhythmic susceptibility compared to the single mutants. The scaffold protein, ZO-1, was reduced at the ICD in N-cadherin heterozygous cardiomyocytes providing a possible explanation for the reduction in Cx43 plaque size. These data provide further support for the intimate relationship between N-cadherin and Cx43 in the heart, and suggest that germline mutations in the human N-cadherin (Cdh2) gene may predispose patients to increased risk of cardiac arrhythmias.

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Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy

Abstract: These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.

Cited by 49 publications

References 29 publications

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility

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