Cardiomyocyte cohesion is increased after ADAM17 inhibition

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Genetics

Background:

• Disintegrin And Metalloprotease (ADAM) proteins are implicated in cardiac diseases.
• ADAM17 cleaves desmoglein 2 (DSG2), a protein crucial for desmosomal stability, which is impaired in arrhythmogenic cardiomyopathy (AC).

Purpose of the Study:

• To investigate the role of ADAM17 in AC pathogenesis.
• To explore the potential of ADAM17 inhibition as a therapeutic strategy for AC.

Main Methods:

• Utilized the murine Jup-/- AC model and HL-1 cardiomyocytes.
• Administered acute inhibition of ADAM17.
• Assessed cardiomyocyte cohesion, DSG2 and desmoplakin (DP) localization, and desmosomal complex assembly.

Main Results:

• ADAM17 inhibition enhanced cardiomyocyte cohesion in both wild-type and AC model mice.
• Inhibition led to increased DSG2 and DP localization at the cardiomyocyte membrane.
• No significant changes were observed in overall desmosomal assembly or complex formation.

Conclusions:

• Acute ADAM17 inhibition may stabilize desmosomal adhesion by reducing DSG2 cleavage.
• This stabilization enhances cardiomyocyte cohesion, suggesting a potential therapeutic avenue for AC.
• The findings suggest conserved mechanisms of ADAM17 involvement in AC pathogenesis.