Transforming Growth Factor-<i>β</i> Stimulates the Expression of Desmosomal Proteins in Bronchial Epithelial Cells

Yoshida, Masami; Romberger, Debra J.; Illig, Mary; Takizawa, Hajime; Sacco, Oliviero; Spurzem, John R.; Sisson, Joseph H.; Rennard, Stephen I.; Beckmann, Joe D.

doi:10.1165/ajrcmb/6.4.439

Cited by 42 publications

(21 citation statements)

References 39 publications

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“…cDNA microarray analysis performed on RNA from cardiac fibroblasts incubated in the presence or in the absence of exogenous TGFhs revealed increased expression of different genes, including Plakoglobin [37]. Yoshida et al reported that TGFh1 exposure of cultured airway epithelial cells increases the content of desmoplakins I and II, thus suggesting that regulation of cell-cell junctional complexes may be an important effect exerted by TGFhs [38]. Therefore, overexpression of TGFh3, caused by UTRs mutations, might affect as well cell-to-cell junction stability, leading to a final outcome similar to that observed in ARVD8 [8] and in the ARVC-related Naxos syndrome [10].…”

Section: Discussionmentioning

confidence: 99%

Regulatory mutations in transforming growth factor-?3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

Beffagna

Occhi

Nava

et al. 2005

Cardiovascular Research

385

242

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Section: Discussionmentioning

confidence: 99%

Regulatory mutations in transforming growth factor-?3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

Beffagna

Occhi

Nava

et al. 2005

Cardiovascular Research

385

242

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“…On the basis of these ultrastructural findings and of the histological demonstration of myocardial atrophy in patients who underwent endomyocardial biopsy, we can postulate that in desmosomal cardiomyopathies (ie, Naxos syndrome, Carvajal syndrome, and ARVC), 8,10 -12,14 -16 impaired cell-to-cell adhesion leads to myocyte detachment, cell death, and fibrofatty repair. 17,32 Moreover, because TGF␤3 could modulate expression of genes encoding desmosomal proteins in different cell types, 33 the same pathogenic mechanism could be advocated in ARVD1 patients. 12 From the clinical point of view, in our series of unrelated DSG2 mutation carriers, a typical form of ARVC was documented with left ventricular involvement in almost half of the cases.…”

Section: Effect Of the Dsg2 Mutations At The Cellular Levelmentioning

confidence: 99%

Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy

et al. 2006

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Background-Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results-In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-␤3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions-This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVCunrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.

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“…It has been reported that TGF-␤3, the only one of these genes not encoding a desmosomal protein, regulates the expression of desmosomal genes including JUP and PKP2. 23 Therefore, desmosomal protein dysfunction appears to be a "final common pathway" playing an important role in the development of ARVD/C. 24,25 Desmosomes are specialized cell-cell adhesion structures abundant in tissues (primarily skin and heart) undergoing high mechanical stress, connecting intermediate filaments to the cell membrane.…”

Section: Yang Et Al Desmoplakin Mutations and Arvd/c 651mentioning

confidence: 99%

Desmosomal Dysfunction due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Zhao¹,

Bowles²,

Scherer³

et al. 2006

Circulation Research

287

213

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Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive degeneration of the right ventricular myocardium, ventricular arrhythmias, fibrous-fatty replacement, and increased risk of sudden death. Mutations in 6 genes, including 4 encoding desmosomal proteins (Junctional plakoglobin (JUP), Desmoplakin (DSP), Plakophilin 2, and Desmoglein 2), have been identified in patients with ARVD/C. Mutation analysis of 66 probands identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between those DSP missense mutations and ARVD/C, we performed in vitro and in vivo analyses of the mutated proteins. Unlike wild-type (WT) DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in desomosome-forming cell line and failed to bind to and coimmunoprecipitate JUP. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes have failed: analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. We were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or WT DSP. Whereas mice overexpressing WT DSP had no detectable histologic, morphological, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs (IDs) and marked ultra-structural changes of IDs. These data suggest DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and DSP abnormalities result in ARVD/C by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development.

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Transforming Growth Factor-β Stimulates the Expression of Desmosomal Proteins in Bronchial Epithelial Cells

Cited by 42 publications

References 39 publications

Regulatory mutations in transforming growth factor-?3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

Regulatory mutations in transforming growth factor-?3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy

Desmosomal Dysfunction due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

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