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Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy
Camilla Schinner, … , Thomas D. Mueller, Jens Waschke
Camilla Schinner, … , Thomas D. Mueller, Jens Waschke
Published May 7, 2020
Citation Information: JCI Insight. 2020;5(9):e130141. https://doi.org/10.1172/jci.insight.130141.
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Research Article Cardiology

Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy

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Abstract

Arrhythmogenic cardiomyopathy (AC) is a genetic disease causing arrhythmia and sudden cardiac death with only symptomatic therapy available at present. Mutations of desmosomal proteins, including desmoglein-2 (Dsg2) and plakoglobin (Pg), are the major cause of AC and have been shown to lead to impaired gap junction function. Recent data indicated the involvement of anti-Dsg2 autoantibodies in AC pathogenesis. We applied a peptide to stabilize Dsg2 binding similar to a translational approach to pemphigus, which is caused by anti-desmoglein autoantibodies. We provide evidence that stabilization of Dsg2 binding by a linking peptide (Dsg2-LP) is efficient to rescue arrhythmia in an AC mouse model immediately upon perfusion. Dsg2-LP, designed to cross-link Dsg2 molecules in proximity to the known binding pocket, stabilized Dsg2-mediated interactions on the surface of living cardiomyocytes as revealed by atomic force microscopy and induced Dsg2 oligomerization. Moreover, Dsg2-LP rescued disrupted cohesion induced by siRNA-mediated Pg or Dsg2 depletion or l-tryptophan, which was applied to impair overall cadherin binding. Dsg2-LP rescued connexin-43 mislocalization and conduction irregularities in response to impaired cardiomyocyte cohesion. These results demonstrate that stabilization of Dsg2 binding by Dsg2-LP can serve as a novel approach to treat arrhythmia in patients with AC.

Authors

Camilla Schinner, Bernd Markus Erber, Sunil Yeruva, Angela Schlipp, Vera Rötzer, Ellen Kempf, Sebastian Kant, Rudolf E. Leube, Thomas D. Mueller, Jens Waschke

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Figure 1

Dsg2-LP reduces arrhythmias in perfused AC-like mouse hearts.

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Dsg2-LP reduces arrhythmias in perfused AC-like mouse hearts.
(A) Modeli...
(A) Modeling of the potential cis interaction between 2 Dsg2 extracellular 1 domains (EC1s). Dashed line indicates 2-fold symmetry axis of the 2 EC1s. (B) Structure of the monomeric peptide (Dsg2-IP) fitted to the EC1 of Dsg2. Residues potentially in contact with the peptide are shown as sticks and numbered in 3-letter code accordingly. (C) Magnification of B. Dsg2-IP shown; C atoms colored in cyan. Interface residues located on the central β-sheet are shown as sticks with C atoms colored in green. (D and F) Representative time course of duration of R-R intervals of perfused hearts from Pg-KO mice with AC-like phenotype under baseline conditions and after addition of Dsg2-LP. Every dot indicates the duration of 1 beat-to-beat interval plotted against perfusion time. VE-Cad-LP served as peptide control. Right panel shows representative ECG traces from indicated time points. (E and G) Analysis of SDNN derived from Pg-KO hearts treated as described in D and F. (H and I) Representative time course of duration of R-R intervals with analysis of the SDNN of perfused hearts from WT mice under baseline conditions and after addition of Dsg2-LP (n = 5 mice for Dsg-LP and Pg-KO and WT; n = 3 mice for VE-Cad-LP) n.s., P ≥ 0.05, *P < 0.05. Two-tailed paired Student’s t test with 95% confidence level was performed. Black lines indicate paired values.

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