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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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Cardiac morphology and histology of 13-week-old male DSG2mt/mt mice. Note the pronounced dilation of the heart chambers in (a, b) and the dilated atria (arrows in a). c Representative Kossa stain of an area in the ventricular wall marked by rectangles in b. The black silver deposits within such a fibrotic lesion indicate the presence of calcified, necrotic cardiomyocytes. d Representative hematoxylin/eosin stain of an area with cardiomyocytes surrounded by fibrous tissue. Note the dysmorphic nuclei of cardiomyocytes (arrowheads) adjacent to fibrocytes. Scale bars: 5 mm in a, same magnification in b; 200 μm in c, same magnification in d
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Fig3: Cardiac morphology and histology of 13-week-old male DSG2mt/mt mice. Note the pronounced dilation of the heart chambers in (a, b) and the dilated atria (arrows in a). c Representative Kossa stain of an area in the ventricular wall marked by rectangles in b. The black silver deposits within such a fibrotic lesion indicate the presence of calcified, necrotic cardiomyocytes. d Representative hematoxylin/eosin stain of an area with cardiomyocytes surrounded by fibrous tissue. Note the dysmorphic nuclei of cardiomyocytes (arrowheads) adjacent to fibrocytes. Scale bars: 5 mm in a, same magnification in b; 200 μm in c, same magnification in d

Mentions: Anatomically, dilation of both ventricles and in some cases also dilated atria were readily apparent in dissected female and male mutants (Figs. 2d, 3a, b). Furthermore, heart weight was significantly increased (Table 2). In one case of sudden death, rupture of the right ventricle was detected. Anatomical, histological and clinical parameters did not change upon successive inbreeding and backcrossing against C57BL/6J (online resource 1 and 2; unpublished data).Fig. 3


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)

Cardiac morphology and histology of 13-week-old male DSG2mt/mt mice. Note the pronounced dilation of the heart chambers in (a, b) and the dilated atria (arrows in a). c Representative Kossa stain of an area in the ventricular wall marked by rectangles in b. The black silver deposits within such a fibrotic lesion indicate the presence of calcified, necrotic cardiomyocytes. d Representative hematoxylin/eosin stain of an area with cardiomyocytes surrounded by fibrous tissue. Note the dysmorphic nuclei of cardiomyocytes (arrowheads) adjacent to fibrocytes. Scale bars: 5 mm in a, same magnification in b; 200 μm in c, same magnification in d
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105238&req=5

Fig3: Cardiac morphology and histology of 13-week-old male DSG2mt/mt mice. Note the pronounced dilation of the heart chambers in (a, b) and the dilated atria (arrows in a). c Representative Kossa stain of an area in the ventricular wall marked by rectangles in b. The black silver deposits within such a fibrotic lesion indicate the presence of calcified, necrotic cardiomyocytes. d Representative hematoxylin/eosin stain of an area with cardiomyocytes surrounded by fibrous tissue. Note the dysmorphic nuclei of cardiomyocytes (arrowheads) adjacent to fibrocytes. Scale bars: 5 mm in a, same magnification in b; 200 μm in c, same magnification in d
Mentions: Anatomically, dilation of both ventricles and in some cases also dilated atria were readily apparent in dissected female and male mutants (Figs. 2d, 3a, b). Furthermore, heart weight was significantly increased (Table 2). In one case of sudden death, rupture of the right ventricle was detected. Anatomical, histological and clinical parameters did not change upon successive inbreeding and backcrossing against C57BL/6J (online resource 1 and 2; unpublished data).Fig. 3

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