Limits...
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.

Show MeSH

Related in: MedlinePlus

Two-week-old DSG2mt/mt mice present variable cardiac phenotypes. In situ images of hearts (a–c), Kossa stains of histological sections (d–f) and cleaved caspase 3-immunohistology (g–i) are shown for heterozygous DSG2mt/wt mice (a, d, g) and for homozygous DSG2mt/mt mice either without visible fibrotic foci (b, e, f) or with extensive fibrotic lesions (+fib.; c, f, i). Note the positive Kossa reaction in the large fibrotic area in (f) and the increase of cleaved caspase-3 positive cells (arrowheads) within a fibrotic lesion (le; i) of a DSG2mt/mt mouse with fibrosis. Scale bars: 5 mm in a (same magnification in b, c), 200 μm in (d) (same magnification in e, f), 100 μm in (g) (same magnification in h, i)
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3105238&req=5

Fig6: Two-week-old DSG2mt/mt mice present variable cardiac phenotypes. In situ images of hearts (a–c), Kossa stains of histological sections (d–f) and cleaved caspase 3-immunohistology (g–i) are shown for heterozygous DSG2mt/wt mice (a, d, g) and for homozygous DSG2mt/mt mice either without visible fibrotic foci (b, e, f) or with extensive fibrotic lesions (+fib.; c, f, i). Note the positive Kossa reaction in the large fibrotic area in (f) and the increase of cleaved caspase-3 positive cells (arrowheads) within a fibrotic lesion (le; i) of a DSG2mt/mt mouse with fibrosis. Scale bars: 5 mm in a (same magnification in b, c), 200 μm in (d) (same magnification in e, f), 100 μm in (g) (same magnification in h, i)

Mentions: Contiguous fibrotic lesions were examined next. A subset of DSG2mt/mt mice presented extensive lesions with necrotic calcinosis already at 2 weeks (Fig. 6c, f). Furthermore, cells expressing activated caspase-3 were also observed indicating apoptotic cell death (Fig. 6i). Significantly elevated Ki67-staining was detected within these lesions (54.4 ± 5.6%; Fig. 5 m) in comparison to interstitial cells in areas away from the lesion or in age-matched DSG2wt/wt and DSG2wt/mt hearts (P < 0.0001). Of note, the number of proliferating cells within such lesions was significantly higher in 2-week-old than in 8- and 13-week-old animals (Fig. 5j, m–o). The cells within the lesions were rounded in young animals and spindle shaped in the older mice (compare, Fig. 5m–o).Fig. 6


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)

Two-week-old DSG2mt/mt mice present variable cardiac phenotypes. In situ images of hearts (a–c), Kossa stains of histological sections (d–f) and cleaved caspase 3-immunohistology (g–i) are shown for heterozygous DSG2mt/wt mice (a, d, g) and for homozygous DSG2mt/mt mice either without visible fibrotic foci (b, e, f) or with extensive fibrotic lesions (+fib.; c, f, i). Note the positive Kossa reaction in the large fibrotic area in (f) and the increase of cleaved caspase-3 positive cells (arrowheads) within a fibrotic lesion (le; i) of a DSG2mt/mt mouse with fibrosis. Scale bars: 5 mm in a (same magnification in b, c), 200 μm in (d) (same magnification in e, f), 100 μm in (g) (same magnification in h, i)
© Copyright Policy
Related In: Results  -  Collection

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

Fig6: Two-week-old DSG2mt/mt mice present variable cardiac phenotypes. In situ images of hearts (a–c), Kossa stains of histological sections (d–f) and cleaved caspase 3-immunohistology (g–i) are shown for heterozygous DSG2mt/wt mice (a, d, g) and for homozygous DSG2mt/mt mice either without visible fibrotic foci (b, e, f) or with extensive fibrotic lesions (+fib.; c, f, i). Note the positive Kossa reaction in the large fibrotic area in (f) and the increase of cleaved caspase-3 positive cells (arrowheads) within a fibrotic lesion (le; i) of a DSG2mt/mt mouse with fibrosis. Scale bars: 5 mm in a (same magnification in b, c), 200 μm in (d) (same magnification in e, f), 100 μm in (g) (same magnification in h, i)
Mentions: Contiguous fibrotic lesions were examined next. A subset of DSG2mt/mt mice presented extensive lesions with necrotic calcinosis already at 2 weeks (Fig. 6c, f). Furthermore, cells expressing activated caspase-3 were also observed indicating apoptotic cell death (Fig. 6i). Significantly elevated Ki67-staining was detected within these lesions (54.4 ± 5.6%; Fig. 5 m) in comparison to interstitial cells in areas away from the lesion or in age-matched DSG2wt/wt and DSG2wt/mt hearts (P < 0.0001). Of note, the number of proliferating cells within such lesions was significantly higher in 2-week-old than in 8- and 13-week-old animals (Fig. 5j, m–o). The cells within the lesions were rounded in young animals and spindle shaped in the older mice (compare, Fig. 5m–o).Fig. 6

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