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AIMS: We determined the contribution of the desmosomal cadherin desmoglein-2 to cell-cell cohesion in cardiomyocytes. In the intercalated disc, providing mechanical strength and electrical communication between adjacent cardiomyocytes, desmoglein-2 is closely associated with N-cadherin and gap junctions. METHODS AND RESULTS: We studied intercalated discs of HL-1 cardiomyocytes by immunostaining of desmoglein-2 and N-cadherin. Cohesion was measured using a liberase-based dissociation-assay and compared with cell-free single-molecule atomic force microscopy measurements. L-tryptophan caused irregular desmoglein-2 condensation, weakened cell-cell cohesion and impaired both homophilic desmoglein-2 and N-cadherin trans-interaction, whereas l-phenylalanine had no effect. L-tryptophan did not affect N-cadherin localization and its inhibitory effect on cell-cohesion and desmoglein-2 binding, but not on N-cadherin interaction, was blocked by a desmoglein-specific tandem peptide. Moreover, Ca(2+)-depletion, desmoglein-2 knockdown, a desmoglein-specific single peptide and certain desmoglein-2 mutations associated with arrhythmogenic cardiomyopathy reduced cell-cell cohesion, whereas cell adhesion was strengthened by desmoglein-2 overexpression. Since single peptide did not interfere with N-cadherin trans-interaction, these data indicate that (i) desmoglein-2 binding is crucial for cardiomyocyte cohesion and (ii) L-tryptophan reduced both desmoglein-2 and N-cadherin binding, whereas single and tandem peptide can be used to specifically target desmoglein-2-mediated adhesion. L-tryptophan and single peptide also induced ultrastructural alterations of areae compositae. Functional analyses at the organ level revealed reduced cardiomyocyte function and inefficient response to adrenergic stimulation in both L-tryptophan- and single peptide-challenged murine Langendorff hearts paralleled by redistribution of connexin 43 in L-tryptophan-treated heart slices. CONCLUSION: Our data demonstrate that desmoglein-2 plays a critical role in cardiomyocyte cohesion and function.

Original publication

DOI

10.1093/cvr/cvu206

Type

Journal article

Journal

Cardiovasc Res

Publication Date

01/11/2014

Volume

104

Pages

245 - 257

Keywords

Arrhythmogenic cardiomyopathy, Cardiomyocyte cohesion, Desmoglein-2, Desmosome, Langendorff, Animals, Cadherins, Calcium, Cell Adhesion, Cell Line, Connexin 43, Desmoglein 2, Dose-Response Relationship, Drug, Gap Junctions, Isolated Heart Preparation, Mice, Inbred BALB C, Mutation, Myocytes, Cardiac, Peptides, Receptors, Adrenergic, beta-1, Signal Transduction, Tryptophan