Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy

• DOI: 10.1172/jci.insight.130141
• Publication Date: 2020-05-06T15:01:37Z
• Authors: Camilla Schinner; Bernd Markus Erber; Sunil Yeruva; Angela Schlipp; Vera Rötzer; Ellen Kempf; Sebastian Kant; Rudolf E. Leube; Thomas D. Mueller; Jens Waschke
• Keywords: 0301 basic medicine; Desmoglein 2; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Connexin 43; Cell Adhesion; Animals; Myocytes, Cardiac; Peptides; Arrhythmogenic Right Ventricular Dysplasia; Protein Binding

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.