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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 6

Dsg2-LP stabilizes Dsg2-mediated binding on living cardiomyocytes.

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Dsg2-LP stabilizes Dsg2-mediated binding on living cardiomyocytes.
Repre...
Representative binding event and topography images of AFM force mapping performed with a Dsg2-coated tip on HL-1 cardiomyocytes (A) or cardiomyocytes isolated from Dsg2-KO mice or WT littermates (D, G, and J) treated with Dsg2-LP 30–90 minutes. Cyan line indicates cell-cell border. Every white pixel represents 1 binding event at the respective location. (A) n = 5 independent experiments, scale bar: 1 μm. (D) n = 7 mice, (G) n = 6 mice per phenotype, and (J) n = 6 mice; scale bar: 2 μm. Unbinding forces (B, E, H, and K) and binding frequency (C, F, I, and L) of Dsg2-mediated binding events corresponding to respective panels on the left. Every dot represents the mean value of 1 independent experiment, bars indicate mean ± SD, and black lines connect paired values. *P < 0.05. Two-tailed paired Student’s t test was performed.

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