Stabilization of desmoglein-2 binding rescues arrhythmia in arrhythmogenic cardiomyopathy

Area of Science:

• Cardiovascular Medicine
• Genetics
• Molecular Biology

Background:

• Arrhythmogenic cardiomyopathy (AC) is a genetic heart disease leading to arrhythmia and sudden cardiac death.
• Mutations in desmosomal proteins like desmoglein-2 (Dsg2) are primary causes, impairing gap junction function.
• Emerging evidence suggests anti-Dsg2 autoantibodies contribute to AC pathogenesis.

Purpose of the Study:

• To investigate the therapeutic potential of stabilizing Dsg2 binding using a novel linking peptide (Dsg2-LP).
• To evaluate Dsg2-LP's efficacy in rescuing arrhythmia and restoring cardiomyocyte cohesion in an AC mouse model.

Main Methods:

• Application of a Dsg2-linking peptide (Dsg2-LP) designed to stabilize Dsg2 interactions.
• Assessment of Dsg2 binding stabilization and oligomerization using atomic force microscopy on cardiomyocytes.
• Evaluation of Dsg2-LP's effect on cardiomyocyte cohesion, connexin-43 localization, and conduction in AC models.

Main Results:

• Dsg2-LP efficiently rescued arrhythmia in an AC mouse model upon perfusion.
• The peptide stabilized Dsg2-mediated interactions and induced Dsg2 oligomerization on cardiomyocyte surfaces.
• Dsg2-LP restored disrupted cohesion and corrected connexin-43 mislocalization and conduction irregularities.

Conclusions:

• Stabilization of Dsg2 binding with Dsg2-LP presents a viable therapeutic strategy for AC.
• This approach effectively targets the underlying molecular defects in AC, offering a novel treatment avenue.
• Dsg2-LP demonstrates potential for treating arrhythmia in patients with arrhythmogenic cardiomyopathy.