Cell-Cell Connection to Cardiac Disease

Sheikh, Farah; Ross, Robert S.; Chen, Ju

doi:10.1016/j.tcm.2009.12.001

Cited by 130 publications

(140 citation statements)

References 76 publications

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“…Fascia adherens junctions and desmosomes are essential for the mechanical coupling of myocardial cells. Fascia adherens junctions provide anchorage for actin filaments, and desmosomes provide anchorage for IFs (Sheikh et al, 2009). ROCK2 phosphorylates ERM family proteins, which are cross-linkers of the plasma membrane and actin filaments, and recruits ERM family proteins to plasma membranes (Fukata et al, 1998;Matsui et al, 1998).…”

Section: Cell-cell Adhesion Sitesmentioning

confidence: 99%

Distinct Distribution and Localization of Rho-kinase in Mouse Epithelial, Muscle and Neural Tissues

Iizuka

Kimura

Wang

et al. 2012

Cell Struct. Funct.

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ABSTRACT. The small GTP-binding protein Rho plays a crucial role in a wide variety of cellular functions through various effector proteins. Rho-kinase is a key effector protein of Rho, which is composed of two isoforms, ROCK1 and ROCK2. To clarify the site of action of ROCK1 and ROCK2, we performed immunofluorescence and immunoelectron microscopic analyses using isoform-specific antibodies in mouse tissues. In the large and small intestines, ROCK1 immunoreactivity was predominantly identified in epithelial cells, and ROCK2 immunoreactivity was negligible. In these epithelial cells, ROCK1 immunoreactivity was distributed on plasma membranes, while ROCK1 immunogold signals were localized at cell-cell contacts and cell adhesion sites, especially at the adherens junctions at the ultrastructural level. In the bladder epithelium, however, ROCK1 and ROCK2 signals were identified at intermediate filaments, and ROCK2 signals were also observed in nuclei. In the three types of muscular cells-smooth, cardiac, and skeletal muscle cells-ROCK1 and ROCK2 also showed differential distribution. ROCK1 signals were localized at actin filaments, plasma membranes, and vesicles near plasma membranes in smooth muscle cells; at the lysosomes in skeletal muscle cells; and were undetectable in cardiac muscle cells. ROCK2 signals were localized at actin filaments and centrosomes in smooth muscle cells, at intercalated discs in cardiac muscle cells, and at Z-discs and sarcoplasmic reticulum in skeletal muscle cells. In the brain, ROCK1 immunoreactivity was distributed in glia, whereas ROCK2 immunoreactivity was observed in neurons. These results indicate that the two isoforms of Rho-kinase distribute differentially to accomplish their specific functions.

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Section: Cell-cell Adhesion Sitesmentioning

confidence: 99%

Distinct Distribution and Localization of Rho-kinase in Mouse Epithelial, Muscle and Neural Tissues

Iizuka

Kimura

Wang

et al. 2012

Cell Struct. Funct.

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“…Cardiac myocyte-to-myocyte adhesion is maintained by desmosomes, adherens junctions and gap junctions, which together comprise the intercalated disc 5 7. The desmosomes have a complex structure that includes adhesion molecules of the cadherin (desmoglein-DSG and desmocollin-DSC), plakin (desmoplakin-DSP) and catenin (plakophilin-PKP and plakoglobin-JUP) families, which link intermediate filaments of the cytoskeleton to the desmosomal cadherins 8 9.…”

Section: Introductionmentioning

confidence: 99%

Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy

et al. 2014

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Background Genotype-phenotype correlations are poorly characterized in arrhythmogenic right ventricular cardiomyopathy (ARVC). We investigated whether carriers of rare variants in desmosomal genes (DC) and titin gene (TTN) display different phenotypes and clinical outcomes, when compared to non-carriers (NT-ND). Methods and Results Thirty-nine ARVC families (173 subjects, 67 affected) with extensive follow up (mean 9 years), prospectively enrolled in the International Familial Cardiomyopathy Registry since 1991, were screened for rare variants in TTN and desmosomal genes (DSP, PKP2, DSG2, DSC2). Multiple clinical and outcome variables were compared between 3 genetic groups (TTN, DC, NT-ND) to define genotype-phenotype associations. Of the 39 ARVC families, 13% (5/39) carried TTN rare variants (11 affected subjects), 13% (5/39) DC (8 affected), while 74% (29/39) were NT-ND (48 affected). Compared to NT-ND, DC had a higher prevalence of inverted T waves in V2-3 (75% vs. 31%, p=0.004), while TTN had more supraventricular arrhythmias (46% vs. 13%, p=0.013) and conduction disease (64% vs. 6% p<0.001). Compared to the NT-ND group, the DC group experienced a worse prognosis (67% vs. 11%, p=0.03) and exhibited a lower survival free from death or heart transplant (59% vs. 95% at 30 years, and 31% vs. 89% at 50 years, HR 9.66, p=0.006), while the TTN group showed an intermediate survival curve (HR 4.26, p=0.037). Conclusions TTN carriers display distinct phenotypic characteristics including a greater risk for supraventricular arrhythmias and conduction disease. Conversely, DC are characterized by negative T waves in anterior leads, severe prognosis, high mortality and morbidity.

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“…The majority of evidence comes from studies performed on patients harboring the cardiac muscle disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), which is primarily thought to be caused by pathogenic mutations/defects in genes of the desmosomal cell-cell junction (Sheikh et al, 2009); however, studies have also revealed that patients harboring gap junction mutations also present with specific electrophysiological abnormalities linked to the CCS.…”

Section: Ccs Defects Found In Human Patients With Underlying Defementioning

confidence: 99%

Cell Junctions in the Specialized Conduction System of the Heart

Mezzano

Pellman

Sheikh

2014

Cell Communication & Adhesion

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Anchoring cell junctions are integral in maintaining electro-mechanical coupling of ventricular ‘working’ cardiomyocytes; however, their role in cardiomyocytes of the cardiac conduction system (CCS) remains less clear. Recent studies in genetic mouse models and humans highlight the appearance of these cell junctions alongside gap junctions in the CCS and also show that defects in these structures and their components are associated with conduction impairments in the CCS. Here we outline current evidence supporting an integral relationship between anchoring and gap junctions in the CCS. Specifically we focus on (1) molecular and ultrastructural evidence for cell-cell junctions in specialized cardiomyocytes of the CCS, (2) genetic mouse models specifically targeting cell-cell junction components in the heart which exhibit CCS conduction defects and (3) human clinical studies from patients with cell-cell junction-based diseases that exhibit CCS electrophysiological defects.

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Cell-Cell Connection to Cardiac Disease

Cited by 130 publications

References 76 publications

Distinct Distribution and Localization of Rho-kinase in Mouse Epithelial, Muscle and Neural Tissues

Distinct Distribution and Localization of Rho-kinase in Mouse Epithelial, Muscle and Neural Tissues

Titin and desmosomal genes in the natural history of arrhythmogenic right ventricular cardiomyopathy

Cell Junctions in the Specialized Conduction System of the Heart

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