Desmoglein 2 mutant mice develop cardiac fibrosis and dilation

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-011-0175-y) contains supplementary material, which is available to authorized users.

Desmoglein 2–Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function

“…Live-born homozygous DSG2 MT carriers developed an AC-like phenotype during adolescence. 19,20 The deleted part of Dsg2 includes the most aminoterminal calcium-binding site and is believed to be important for adhesion through homo-and heterophilic desmosomal cadherin interaction. 21 Thus, peptides taken from this domain prevent Dsg2-dependent adhesion, 22 and autoantibodies targeting the corresponding region in Dsg3 induce cell dissociation in pemphigus vulgaris.…”

Intercellular Connections in the Heart: The Intercalated Disc

“…Nonetheless, the importance of both desmoglein and desmocollin in cardiac function is further evidenced by the numerous mutations identified in their respective genes that lead to cardiomyopathies, mainly manifested as ARVC. Consistent with this, mice harbouring a mutation resulting in a truncated form of desmoglein-2 develop ARVC (Krusche et al, 2011), while a systemic knockout mouse model of desmoglein-2 is embryonic lethal (Eshkind et al, 2002).…”

Special issue Heidelberg Heart II: Abstracts of oral and poster presentations

“…This coincided with the time-point at which junctional gap-widening was observed, suggesting that ID integrity is required for proper electrical conduction. (Krusche, Holthöfer et al, 2011). Since osteopontin (OPN) is involved in calcification, inflammation, and cardiac fibrosis (Renault et al 2010;Matsui et al 2004;Okamoto et al 2011), we studied expression and tissue distribution of OPN and its receptor, the CD44 antigen, which is involved in leukocyte recruitment (Weber et al 1996;DeGrendele et al 1996).…”

“…Our modified multifunctional bioreactor allows for threedimensional culturing of human cord-blood-derived unrestricted somatic stem cells on pericardial stented valves with the support of magnetic cell guidance. Mice carrying a deletion of the extracellular EC1/EC2-domains of the desmosomal cadherin desmoglein 2 develop dilated cardiomyopathy with arrhythmia and fibrosis (Krusche, Holthöfer et al 2011). The mutant desmoglein 2 is still targeted to the intercalated disc region together with the other desmosomal proteins, albeit at reduced amounts (Krusche, Holthöfer et al 2011).…”

“…Mice carrying a deletion of the extracellular EC1/EC2-domains of the desmosomal cadherin desmoglein 2 develop dilated cardiomyopathy with arrhythmia and fibrosis (Krusche, Holthöfer et al 2011). The mutant desmoglein 2 is still targeted to the intercalated disc region together with the other desmosomal proteins, albeit at reduced amounts (Krusche, Holthöfer et al 2011). This suggests that altered adhesion may be responsible for initiation of the disease process upon continued mechanical stress.…”