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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 7

Dsg2-LP enhances formation of Dsg2 oligomers.

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Dsg2-LP enhances formation of Dsg2 oligomers.
(A) Membrane-impermeable c...
(A) Membrane-impermeable cross-linking with sulfo-EGS performed after 24-hour treatment with Dsg2-LP in HL-1 cells. Western blot analyses were done for Dsg2 and N-Cad. α-Tubulin (α-Tub) served as loading control. Representative image of 4 repeated experiments. (B) Densitometric quantification of Dsg2 and N-Cad bands showing the ratio of cross-linked proteins to total protein. n = 4. *P < 0.05. Two-tailed paired Student’s t test with 95% confidence levels was performed.

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