title: Histological and ultrastructural abnormalities in murine desmoglein 2-mutant hearts.
abstract: Mice carrying a deletion of the adhesive extracellular domain of the desmosomal cadherin desmoglein 2 develop an arrhythmogenic right ventricular cardiomyopathylike phenotype with ventricular dilation, fibrosis and arrhythmia. To unravel the sequence of myocardial alterations and to identify potential pathomechanisms, histological analyses were performed on mutant hearts from the juvenile to the adult state, i.e., between 2 and 13 weeks. At an age of 2 weeks 30% of mutants presented lesions,which were visible as white plaques on the heart surface or in the septum. From 4 weeks onwards, all mutants displayed a cardiac phenotype. Dying cardiomyocytes with calcification were found in lesions of all ages. But lesions of young mutant animals contained high amounts of CD45+ immune cells and little collagen fibers, whereas lesions of the older animals were collagen-rich and harbored only a small but still significantly increased number of CD45+ cells. Electron microscopy further showed that distinct desmosomes cannot be distinguished in intercalated discs of mutant hearts. Widening of the intercellular cleft and even complete dissociation of intercalated discs were often observed close to lesions. Disturbed sarcomer structure, altered Z-discs, multiple autophagic vacuoles and swollen mitochondria were other prominent pathological features. Taken together, the following scenario is suggested: mutant desmoglein 2 cannot fully support the increased mechanical requirements placed on intercalated disc adhesion during postnatal heart development, resulting in compromised adhesion and cell stress. This induces cardiomyocyte death, aseptic inflammation and fibrotic replacement. The acute stage of scar formation is followed by permanent impairment of the cardiac function.
authors.affiliation: Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kant
authors.forename: Philipp
authors.initials: P
authors.lastname: Krull
authors.forename: Sabine
authors.initials: S
authors.lastname: Eisner
authors.forename: Rudolf E
authors.initials: RE
authors.lastname: Leube
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Krusche
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology*; D051301:Desmoglein 2 / Q000235:genetics*; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D051301:Desmoglein 2