Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell-cell adhesion

Area of Science:

• Cardiovascular Biology
• Cellular Mechanics
• Molecular Cardiology

Background:

• Arrhythmogenic right ventricular cardiomyopathy (ARVC) is often associated with mutations in desmosomal proteins.
• This suggests a potential role for altered intercellular adhesion in ARVC pathogenesis.

Purpose of the Study:

• To investigate the mechanical properties and molecular responses to shear stress in cardiac myocytes with mutations in plakoglobin and plakophilin, desmosomal proteins implicated in ARVC.
• To elucidate the role of these mutations in myocyte apoptosis and cellular signaling pathways.

Main Methods:

• Cardiac myocytes expressing mutant plakoglobin or plakophilin were subjected to oscillatory shear stress.
• Cell-cell adhesion, protein localization at junctions, myocyte apoptosis, and responses to a GSK3β inhibitor (SB216763) were analyzed.

Main Results:

• Mutant plakoglobin and plakophilin did not affect basal cell-cell adhesion but impaired the normal increase of junctional plakoglobin and N-cadherin under shear stress.
• Cells with mutant plakoglobin exhibited increased apoptosis, particularly under shear stress.
• Abnormal responses to shear stress were reversed by GSK3β inhibition.

Conclusions:

• Desmosomal mutations in ARVC do not significantly alter cell mechanical properties but lead to aberrant myocyte responses to mechanical stress.
• A mechanism involving GSK3β appears central to this abnormal response.
• These findings may explain exercise-induced exacerbations in ARVC patients.