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Desmoglein 2 mutant mice develop cardiac fibrosis and dilation.

Krusche CA, Holthöfer B, Hofe V, van de Sandt AM, Eshkind L, Bockamp E, Merx MW, Kant S, Windoffer R, Leube RE - Basic Res. Cardiol. (2011)

Bottom Line: Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed.Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue.Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany. ckrusche@ukaachen.de

ABSTRACT
Desmosomes are cell-cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2.

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DSG2 mutation induces fibrosis in both ventricles. Hearts were dissected from wild-type and mutant mice carrying two DSG2mt alleles. Histological sections were either stained with hematoxylin/eosin (a–f) and azan (g, h) or were incubated with antibodies directed against the connective tissue marker vimentin and processed for indirect immunofluorescence microscopy (i, j). Note the increased presence of connective tissue in DSG2mt/mt mice. In addition to diffuse fibrosis, large fibrotic scars are visible in the ventricular walls (arrows in b). The magnification is the same in a and b, c–f (scale bar in d, 100 μm) and g–j (scale bar in h, 100 μm)
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Fig4: DSG2 mutation induces fibrosis in both ventricles. Hearts were dissected from wild-type and mutant mice carrying two DSG2mt alleles. Histological sections were either stained with hematoxylin/eosin (a–f) and azan (g, h) or were incubated with antibodies directed against the connective tissue marker vimentin and processed for indirect immunofluorescence microscopy (i, j). Note the increased presence of connective tissue in DSG2mt/mt mice. In addition to diffuse fibrosis, large fibrotic scars are visible in the ventricular walls (arrows in b). The magnification is the same in a and b, c–f (scale bar in d, 100 μm) and g–j (scale bar in h, 100 μm)

Mentions: In dissected hearts of mutant mice, fibrotic lesions of various size and different shapes, often in the form of striations, were frequently seen. In some instances, the entire ventricular wall was completely replaced by fibrotic scar tissue resulting in substantial wall thinning (e.g., Fig. 4b, d). Kossa-positive calcifications were often found in fibrotic lesions and scars (Fig. 3c). Furthermore, groups of cardiomyocytes embedded in fibrous tissue and cardiomyocytes with dysmorphic nuclei were noted (Fig. 3d). Histological analyses further revealed different degrees of fibrosis in both ventricular walls and the septum (Fig. 4b, d, f). Staining with azan and anti-vimentin antibodies further supported these findings (e.g., Fig. 4h, j). Extensive infiltrates of immune cells were not seen except for scattered immune cells in a few regions.Fig. 4


Desmoglein 2 mutant mice develop cardiac fibrosis and dilation.

Krusche CA, Holthöfer B, Hofe V, van de Sandt AM, Eshkind L, Bockamp E, Merx MW, Kant S, Windoffer R, Leube RE - Basic Res. Cardiol. (2011)

DSG2 mutation induces fibrosis in both ventricles. Hearts were dissected from wild-type and mutant mice carrying two DSG2mt alleles. Histological sections were either stained with hematoxylin/eosin (a–f) and azan (g, h) or were incubated with antibodies directed against the connective tissue marker vimentin and processed for indirect immunofluorescence microscopy (i, j). Note the increased presence of connective tissue in DSG2mt/mt mice. In addition to diffuse fibrosis, large fibrotic scars are visible in the ventricular walls (arrows in b). The magnification is the same in a and b, c–f (scale bar in d, 100 μm) and g–j (scale bar in h, 100 μm)
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105238&req=5

Fig4: DSG2 mutation induces fibrosis in both ventricles. Hearts were dissected from wild-type and mutant mice carrying two DSG2mt alleles. Histological sections were either stained with hematoxylin/eosin (a–f) and azan (g, h) or were incubated with antibodies directed against the connective tissue marker vimentin and processed for indirect immunofluorescence microscopy (i, j). Note the increased presence of connective tissue in DSG2mt/mt mice. In addition to diffuse fibrosis, large fibrotic scars are visible in the ventricular walls (arrows in b). The magnification is the same in a and b, c–f (scale bar in d, 100 μm) and g–j (scale bar in h, 100 μm)
Mentions: In dissected hearts of mutant mice, fibrotic lesions of various size and different shapes, often in the form of striations, were frequently seen. In some instances, the entire ventricular wall was completely replaced by fibrotic scar tissue resulting in substantial wall thinning (e.g., Fig. 4b, d). Kossa-positive calcifications were often found in fibrotic lesions and scars (Fig. 3c). Furthermore, groups of cardiomyocytes embedded in fibrous tissue and cardiomyocytes with dysmorphic nuclei were noted (Fig. 3d). Histological analyses further revealed different degrees of fibrosis in both ventricular walls and the septum (Fig. 4b, d, f). Staining with azan and anti-vimentin antibodies further supported these findings (e.g., Fig. 4h, j). Extensive infiltrates of immune cells were not seen except for scattered immune cells in a few regions.Fig. 4

Bottom Line: Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed.Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue.Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Wendlingweg 2, Aachen, Germany. ckrusche@ukaachen.de

ABSTRACT
Desmosomes are cell-cell adhesion sites and part of the intercalated discs, which couple adjacent cardiomyocytes. The connection is formed by the extracellular domains of desmosomal cadherins that are also linked to the cytoskeleton on the cytoplasmic side. To examine the contribution of the desmosomal cadherin desmoglein 2 to cardiomyocyte adhesion and cardiac function, mutant mice were prepared lacking a part of the extracellular adhesive domain of desmoglein 2. Most live born mutant mice presented normal overall cardiac morphology at 2 weeks. Some animals, however, displayed extensive fibrotic lesions. Later on, mutants developed ventricular dilation leading to cardiac insufficiency and eventually premature death. Upon histological examination, cardiomyocyte death by calcifying necrosis and replacement by fibrous tissue were observed. Fibrotic lesions were highly proliferative in 2-week-old mutants, whereas the fibrotic lesions of older mutants showed little proliferation indicating the completion of local muscle replacement by scar tissue. Disease progression correlated with increased mRNA expression of c-myc, ANF, BNF, CTGF and GDF15, which are markers for cardiac stress, remodeling and heart failure. Taken together, the desmoglein 2-mutant mice display features of dilative cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy, an inherited human heart disease with pronounced fibrosis and ventricular arrhythmias that has been linked to mutations in desmosomal proteins including desmoglein 2.

Show MeSH
Related in: MedlinePlus