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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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Markers of heart failure are increased in DSG2mt/mt mice. Cardiac ANF, BNF, c-myc, CTGF and GDF15 mRNA expression was assessed by real time RT-PCR in 2-, 8- and 13-week-old DSG2wt/wt, DSG2wt/mt and DSG2mt/mt mice. Each column summarizes the data of three to seven animals (mean ± SEM). Hydroxymethylbilane synthase (HMBS) was used as housekeeping gene control. Unaltered regulator of G protein signaling 2 (RGS2) mRNA expression rules out a systematic error of the RT-PCR (p–r). Results of the post hoc Bonferroni tests: *P < 0.05, **P < 0.01, ***P < 0.001. Statistical analysis of mRNA expression data showing no significant differences: aP = 0.3409; dP = 0.0812; gP = 0.1055; mP = 0.1466; pP = 0.820; qP = 0.1837; rP = 0.1623
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Fig7: Markers of heart failure are increased in DSG2mt/mt mice. Cardiac ANF, BNF, c-myc, CTGF and GDF15 mRNA expression was assessed by real time RT-PCR in 2-, 8- and 13-week-old DSG2wt/wt, DSG2wt/mt and DSG2mt/mt mice. Each column summarizes the data of three to seven animals (mean ± SEM). Hydroxymethylbilane synthase (HMBS) was used as housekeeping gene control. Unaltered regulator of G protein signaling 2 (RGS2) mRNA expression rules out a systematic error of the RT-PCR (p–r). Results of the post hoc Bonferroni tests: *P < 0.05, **P < 0.01, ***P < 0.001. Statistical analysis of mRNA expression data showing no significant differences: aP = 0.3409; dP = 0.0812; gP = 0.1055; mP = 0.1466; pP = 0.820; qP = 0.1837; rP = 0.1623

Mentions: The expression of well-established cardiac stress and heart failure markers [14, 16] was examined at 2, 8 and 13 weeks by real time RT-PCR to assess the consequences of DSG2 mutation at the molecular level. At 2 weeks, cardiac connective tissue growth factor (CTGF) mRNA was significantly upregulated. In addition, growth differentiation factor 15 (GDF15) and c-myc mRNA were increased (Fig. 7). When 2-week-old DSG2mt/mt mice were further subclassified by visual inspection into those without and those with fibrotic lesions, significantly elevated GDF15 mRNA expression was found in the hearts with fibrotic lesions (3.83 ± 1.42 vs. 0.18 ± 0.03 arbitrary units; Table 3). This suggests that GDF15 mRNA expression is an early indicator of disease progression.Fig. 7


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)

Markers of heart failure are increased in DSG2mt/mt mice. Cardiac ANF, BNF, c-myc, CTGF and GDF15 mRNA expression was assessed by real time RT-PCR in 2-, 8- and 13-week-old DSG2wt/wt, DSG2wt/mt and DSG2mt/mt mice. Each column summarizes the data of three to seven animals (mean ± SEM). Hydroxymethylbilane synthase (HMBS) was used as housekeeping gene control. Unaltered regulator of G protein signaling 2 (RGS2) mRNA expression rules out a systematic error of the RT-PCR (p–r). Results of the post hoc Bonferroni tests: *P < 0.05, **P < 0.01, ***P < 0.001. Statistical analysis of mRNA expression data showing no significant differences: aP = 0.3409; dP = 0.0812; gP = 0.1055; mP = 0.1466; pP = 0.820; qP = 0.1837; rP = 0.1623
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getmorefigures.php?uid=PMC3105238&req=5

Fig7: Markers of heart failure are increased in DSG2mt/mt mice. Cardiac ANF, BNF, c-myc, CTGF and GDF15 mRNA expression was assessed by real time RT-PCR in 2-, 8- and 13-week-old DSG2wt/wt, DSG2wt/mt and DSG2mt/mt mice. Each column summarizes the data of three to seven animals (mean ± SEM). Hydroxymethylbilane synthase (HMBS) was used as housekeeping gene control. Unaltered regulator of G protein signaling 2 (RGS2) mRNA expression rules out a systematic error of the RT-PCR (p–r). Results of the post hoc Bonferroni tests: *P < 0.05, **P < 0.01, ***P < 0.001. Statistical analysis of mRNA expression data showing no significant differences: aP = 0.3409; dP = 0.0812; gP = 0.1055; mP = 0.1466; pP = 0.820; qP = 0.1837; rP = 0.1623
Mentions: The expression of well-established cardiac stress and heart failure markers [14, 16] was examined at 2, 8 and 13 weeks by real time RT-PCR to assess the consequences of DSG2 mutation at the molecular level. At 2 weeks, cardiac connective tissue growth factor (CTGF) mRNA was significantly upregulated. In addition, growth differentiation factor 15 (GDF15) and c-myc mRNA were increased (Fig. 7). When 2-week-old DSG2mt/mt mice were further subclassified by visual inspection into those without and those with fibrotic lesions, significantly elevated GDF15 mRNA expression was found in the hearts with fibrotic lesions (3.83 ± 1.42 vs. 0.18 ± 0.03 arbitrary units; Table 3). This suggests that GDF15 mRNA expression is an early indicator of disease progression.Fig. 7

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