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Desmoglein-2 interaction is crucial for cardiomyocyte cohesion and function.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2014 Nov 01; Vol. 104 (2), pp. 245-57. Date of Electronic Publication: 2014 Sep 11. - Publication Year :
- 2014
-
Abstract
- 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.<br />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.<br />Conclusion: Our data demonstrate that desmoglein-2 plays a critical role in cardiomyocyte cohesion and function.<br /> (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Cadherins metabolism
Calcium metabolism
Cell Line
Connexin 43 metabolism
Desmoglein 2 antagonists & inhibitors
Desmoglein 2 genetics
Dose-Response Relationship, Drug
Gap Junctions drug effects
Gap Junctions ultrastructure
Isolated Heart Preparation
Mice, Inbred BALB C
Mutation
Myocytes, Cardiac drug effects
Myocytes, Cardiac ultrastructure
Peptides pharmacology
Receptors, Adrenergic, beta-1 metabolism
Signal Transduction
Tryptophan pharmacology
Cell Adhesion drug effects
Desmoglein 2 metabolism
Gap Junctions metabolism
Myocytes, Cardiac metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 104
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 25213555
- Full Text :
- https://doi.org/10.1093/cvr/cvu206