Delineation of structural and molecular pathology in human tissues is essential to understanding the cell-cell junction cardiomyopathies; yet to elucidate mechanisms of disease, we have turned to analysis of mouse models.
The first mouse line we characterized was a model of human desmin-related cardiomyopathy created by X.J. Wang in the laboratory of Jeffrey Robbins . We were attracted to this model because we anticipated that it might exhibit altered desmin-desmo-some interactions and, therefore, recapitulate Carvajal syndrome. Human desmin-related skeletal and cardiomyopathies have been attributed to a 7-amino acid deletion mutation (R173-E179) and several missense mutations in desmin. To determine whether the R173-E179 deletion was sufficient to cause desmin-related cardiomyopathy, Wang et al.  produced transgenic mice with cardiac-specific expression of the 7-amino acid deletion mutation in desmin (D7-des) implicated in the human disease. In their initial description of this model, they showed that D7-des mice exhibit features of human desmin-related car-diomyopathy including intracellular accumulation of desmin, disruption of the desmin filament network, misalignment of myofibrils, and diminished responsiveness to a-adrenergic agonist stimulation .
To test the hypothesis that expression of D7-des disrupts the linkage between desmosomes and the cy-toskeleton and leads to remodeling of gap junctions, we characterized the expression and localization of intercellular junction proteins and searched for an elec-
Fig. 5.4 • Representative confocal immunofluorescence images showing the amount of Cx43 immunoreactive signal at cell-cell junctions in left ventricular myocardium from a nontransgenic control mouse (Con), a transgenic mouse expressing wild-ype desmin (WT-des),and a transgenic mouse expressing D7-des
Fig. 5.4 • Representative confocal immunofluorescence images showing the amount of Cx43 immunoreactive signal at cell-cell junctions in left ventricular myocardium from a nontransgenic control mouse (Con), a transgenic mouse expressing wild-ype desmin (WT-des),and a transgenic mouse expressing D7-des trophysiological phenotype . As predicted by studies of the human cell-cell junction cardiomyopathies, Cx43 signal at intercalated disks was decreased by approximately threefold in D7-des hearts due to significant reductions in both the number and mean size of individual gap junctions (Fig. 5.4). The amount of immunoreactive signal at intercalated disks was also reduced significantly for selected adhesion molecules and linker proteins of both desmosomes and adherens junctions, and desmin-desmosomal interactions were completely disrupted . Quantitative electron microscopy showed decreased gap junction density in D7-des mice, providing independent evidence of gap junction remodeling, but immunoblotting showed no reduction in the total tissue content of Cx43 and mechanical junction proteins. These observations are consistent with findings in Naxos disease, suggesting that diminished localization of cell-cell junction proteins at intercalated disks is not due to insufficient protein expression but, rather, to failure of these proteins to assemble properly within electrical and mechanical junctions. We also showed, using optical mapping, that remodeling of gap junctions in D7-des mice slows ventricular conduction . These results indicate, therefore, that a defect in a protein conventionally thought to fulfill a strictly mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.
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