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.
Highlights
Arrhythmogenic cardiomyopathy (AC) is a hereditary disease with a high risk for sudden cardiac death at a young age
We demonstrate for the first time to our knowledge that stabilization of Dsg2-mediated binding by a specific linking peptide (Dsg2-LP) is capable of rescuing both cardiomyocyte cohesion and gap junctions (GJ)-mediated signal transduction caused by disruption of intercellular adhesion
Our data show that Dsg2 binding by a linking peptide (Dsg2-LP) increased the binding forces of Dsg2-mediated interactions in vitro as well as on living cardiomyocytes and enhanced Dsg2 oligomerization
Summary
Arrhythmogenic cardiomyopathy (AC) is a hereditary disease with a high risk for sudden cardiac death at a young age. Several desmosomal protein–encoding genes, such as for plakophilin-2 (Pkp2), desmoplakin (Dp), plakoglobin (Pg), desmocollin-2 (Dsc2), and desmoglein-2 (Dsg2), as well as a few nondesmosomal genes can be affected by mutations. It is not entirely clear how alterations in the proteins encoded by these genes contribute to arrhythmia, cardiac fibrosis, and subsequent heart failure in patients with AC. A recent study demonstrated antiDsg autoantibodies to be present in patients with AC independent of the underlying mutation These antibodies were capable of inducing an impairment of gap junction function [2]
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