Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function
Research output: Contribution to journal › Article
Colleges, School and Institutes
- Institute of Anatomy and Cell Biology, Ludwig-Maximilians Universität Munich, Pettenkofer Str. 11, Munich 80336, Germany.
- Institute of Cardiovascular Science, University College London and Great Ormond Street Hospital; London UK
- Walter-Brendel-Center of Experimental Medicine, Ludwig-Maximilians Universität Munich, Munich, Germany Munich Heart Alliance, Munich, Germany German Center for Cardiovascular Research, Munich, Germany.
- Institute of Anatomy and Cell Biology, Ludwig-Maximilians Universität Munich, Pettenkofer Str. 11, Munich 80336, Germany email@example.com.
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.
|Number of pages||13|
|Publication status||Published - 1 Nov 2014|
- Animals, Cadherins/metabolism, Calcium/metabolism, Cell Adhesion/drug effects, Cell Line, Connexin 43/metabolism, Desmoglein 2/antagonists & inhibitors, Dose-Response Relationship, Drug, Gap Junctions/drug effects, Isolated Heart Preparation, Mice, Inbred BALB C, Mutation, Myocytes, Cardiac/drug effects, Peptides/pharmacology, Receptors, Adrenergic, beta-1/metabolism, Signal Transduction, Tryptophan/pharmacology