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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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Proliferation (Ki67 immunohistochemistry) of interstitial cells is transiently increased in 8-week-old DSG2mt/mt mice and in fibrotic lesions of young mutant animals. The data in a–j (mean ± SEM) were obtained from three to four animals from parallel breedings at each time point. At the age of 2 weeks only two mt/mt animals were available for sampling from left and right ventricles because of large fibrotic foci in the ventricular wall. Proliferation of interstitial cells detected by Ki67 immunohistochemistry in 2- (a–c) and 13-week-old mice (g–i) was not significantly different between wild-type (wt/wt), heterozygous (wt/mt) and homozygous mutant animals (mt/mt). Results of ANOVA: aP = 0.8729, bP = 0.9394, cP = 0.3574, gP = 0.4773, hP = 0.3932, iP = 0.2726. d–f In 8-week-old DSG2mt/mt mice, proliferation of interstitial cells is significantly elevated compared to wild-type animals (*P < 0.05; **P < 0.01; ***P < 0.001; ANOVA and post hoc Bonferroni tests). j The histogram shows that the number of Ki67-positive cells in fibrotic lesions is significantly higher in 2-week-old DSG2mt/mt mice than in 8- and 13-week-old mutant mice (***P < 0.001). k, l Comparison of Ki67-staining in septum of 8-week-old DSG2mt/mt (k) and DSG2wt/wt (l). Lesion of a 2-week-old (m) and a 13-week-old DSG2mt/mt mouse (n; S scar). o Small fibrotic foci with an increased number of Ki67-positive cells were observed occasionally in 8- to 13-week-old mutants. Arrowheads in k, l, n and o mark Ki67-positive cells. Scale bar in o, 100 μm (same magnification in k–o)
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Fig5: Proliferation (Ki67 immunohistochemistry) of interstitial cells is transiently increased in 8-week-old DSG2mt/mt mice and in fibrotic lesions of young mutant animals. The data in a–j (mean ± SEM) were obtained from three to four animals from parallel breedings at each time point. At the age of 2 weeks only two mt/mt animals were available for sampling from left and right ventricles because of large fibrotic foci in the ventricular wall. Proliferation of interstitial cells detected by Ki67 immunohistochemistry in 2- (a–c) and 13-week-old mice (g–i) was not significantly different between wild-type (wt/wt), heterozygous (wt/mt) and homozygous mutant animals (mt/mt). Results of ANOVA: aP = 0.8729, bP = 0.9394, cP = 0.3574, gP = 0.4773, hP = 0.3932, iP = 0.2726. d–f In 8-week-old DSG2mt/mt mice, proliferation of interstitial cells is significantly elevated compared to wild-type animals (*P < 0.05; **P < 0.01; ***P < 0.001; ANOVA and post hoc Bonferroni tests). j The histogram shows that the number of Ki67-positive cells in fibrotic lesions is significantly higher in 2-week-old DSG2mt/mt mice than in 8- and 13-week-old mutant mice (***P < 0.001). k, l Comparison of Ki67-staining in septum of 8-week-old DSG2mt/mt (k) and DSG2wt/wt (l). Lesion of a 2-week-old (m) and a 13-week-old DSG2mt/mt mouse (n; S scar). o Small fibrotic foci with an increased number of Ki67-positive cells were observed occasionally in 8- to 13-week-old mutants. Arrowheads in k, l, n and o mark Ki67-positive cells. Scale bar in o, 100 μm (same magnification in k–o)

Mentions: Next, proliferation of interstitial cells faraway from fibrotic lesions and proliferation within fibrotic lesions was studied at 2, 8 and 13 weeks by Ki67 immunohistochemistry (Fig. 5). No differences in interstitial cell proliferation were detectable between DSG2wt/wt, DSG2wt/mt and DSG2mt/mt at 2 weeks (Fig. 5a–c). At 8 weeks, the proliferation index of interstitial cells was elevated in all segments of the ventricular walls of DSG2mt/mt mice compared to DSG2wt/wt animals (P < 0.05; Fig. 5d–f, k, l). Then, at 13 weeks, the percentage of proliferating cells did not differ between mutant and wild-type animals anymore (Fig. 5g–i).Fig. 5


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)

Proliferation (Ki67 immunohistochemistry) of interstitial cells is transiently increased in 8-week-old DSG2mt/mt mice and in fibrotic lesions of young mutant animals. The data in a–j (mean ± SEM) were obtained from three to four animals from parallel breedings at each time point. At the age of 2 weeks only two mt/mt animals were available for sampling from left and right ventricles because of large fibrotic foci in the ventricular wall. Proliferation of interstitial cells detected by Ki67 immunohistochemistry in 2- (a–c) and 13-week-old mice (g–i) was not significantly different between wild-type (wt/wt), heterozygous (wt/mt) and homozygous mutant animals (mt/mt). Results of ANOVA: aP = 0.8729, bP = 0.9394, cP = 0.3574, gP = 0.4773, hP = 0.3932, iP = 0.2726. d–f In 8-week-old DSG2mt/mt mice, proliferation of interstitial cells is significantly elevated compared to wild-type animals (*P < 0.05; **P < 0.01; ***P < 0.001; ANOVA and post hoc Bonferroni tests). j The histogram shows that the number of Ki67-positive cells in fibrotic lesions is significantly higher in 2-week-old DSG2mt/mt mice than in 8- and 13-week-old mutant mice (***P < 0.001). k, l Comparison of Ki67-staining in septum of 8-week-old DSG2mt/mt (k) and DSG2wt/wt (l). Lesion of a 2-week-old (m) and a 13-week-old DSG2mt/mt mouse (n; S scar). o Small fibrotic foci with an increased number of Ki67-positive cells were observed occasionally in 8- to 13-week-old mutants. Arrowheads in k, l, n and o mark Ki67-positive cells. Scale bar in o, 100 μm (same magnification in k–o)
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Fig5: Proliferation (Ki67 immunohistochemistry) of interstitial cells is transiently increased in 8-week-old DSG2mt/mt mice and in fibrotic lesions of young mutant animals. The data in a–j (mean ± SEM) were obtained from three to four animals from parallel breedings at each time point. At the age of 2 weeks only two mt/mt animals were available for sampling from left and right ventricles because of large fibrotic foci in the ventricular wall. Proliferation of interstitial cells detected by Ki67 immunohistochemistry in 2- (a–c) and 13-week-old mice (g–i) was not significantly different between wild-type (wt/wt), heterozygous (wt/mt) and homozygous mutant animals (mt/mt). Results of ANOVA: aP = 0.8729, bP = 0.9394, cP = 0.3574, gP = 0.4773, hP = 0.3932, iP = 0.2726. d–f In 8-week-old DSG2mt/mt mice, proliferation of interstitial cells is significantly elevated compared to wild-type animals (*P < 0.05; **P < 0.01; ***P < 0.001; ANOVA and post hoc Bonferroni tests). j The histogram shows that the number of Ki67-positive cells in fibrotic lesions is significantly higher in 2-week-old DSG2mt/mt mice than in 8- and 13-week-old mutant mice (***P < 0.001). k, l Comparison of Ki67-staining in septum of 8-week-old DSG2mt/mt (k) and DSG2wt/wt (l). Lesion of a 2-week-old (m) and a 13-week-old DSG2mt/mt mouse (n; S scar). o Small fibrotic foci with an increased number of Ki67-positive cells were observed occasionally in 8- to 13-week-old mutants. Arrowheads in k, l, n and o mark Ki67-positive cells. Scale bar in o, 100 μm (same magnification in k–o)
Mentions: Next, proliferation of interstitial cells faraway from fibrotic lesions and proliferation within fibrotic lesions was studied at 2, 8 and 13 weeks by Ki67 immunohistochemistry (Fig. 5). No differences in interstitial cell proliferation were detectable between DSG2wt/wt, DSG2wt/mt and DSG2mt/mt at 2 weeks (Fig. 5a–c). At 8 weeks, the proliferation index of interstitial cells was elevated in all segments of the ventricular walls of DSG2mt/mt mice compared to DSG2wt/wt animals (P < 0.05; Fig. 5d–f, k, l). Then, at 13 weeks, the percentage of proliferating cells did not differ between mutant and wild-type animals anymore (Fig. 5g–i).Fig. 5

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