%0 Journal Article %1 schinner2020stabilization %A Schinner, C. %A Erber, B. M. %A Yeruva, S. %A Schlipp, A. %A Rotzer, V. %A Kempf, E. %A Kant, S. %A Leube, R. E. %A Mueller, T. D. %A Waschke, J. %D 2020 %J JCI Insight %K Animals myOwn %N 9 %R 10.1172/jci.insight.130141 %T Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy %U https://www.ncbi.nlm.nih.gov/pubmed/32376797 %V 5 %X 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.

@article{schinner2020stabilization, 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.}, added-at = {2024-02-15T15:08:22.000+0100}, author = {Schinner, C. and Erber, B. M. and Yeruva, S. and Schlipp, A. and Rotzer, V. and Kempf, E. and Kant, S. and Leube, R. E. and Mueller, T. D. and Waschke, J.}, biburl = {https://www.bibsonomy.org/bibtex/240d2576431e0056f687f6dcbfb906fc2/jvsi_all}, doi = {10.1172/jci.insight.130141}, interhash = {8ede6c8d356b0354ade9fd0a795e8d69}, intrahash = {40d2576431e0056f687f6dcbfb906fc2}, issn = {2379-3708 (Electronic) 2379-3708 (Linking)}, journal = {JCI Insight}, keywords = {Animals myOwn}, note = {Schinner, Camilla Erber, Bernd Markus Yeruva, Sunil Schlipp, Angela Rotzer, Vera Kempf, Ellen Kant, Sebastian Leube, Rudolf E Mueller, Thomas D Waschke, Jens eng Research Support, Non-U.S. Gov't 2020/05/08 JCI Insight. 2020 May 7;5(9):e130141. doi: 10.1172/jci.insight.130141.}, number = 9, timestamp = {2024-02-15T15:08:22.000+0100}, title = {Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy}, type = {Journal Article}, url = {https://www.ncbi.nlm.nih.gov/pubmed/32376797}, volume = 5, year = 2020 }