Genotype-Dependent Effects of Mechanical Stretch and GATA4-Targeted Compound 3i-1262 in Cardiomyopathy...

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Genetics

Background:

• Genetic cardiomyopathies, including hypertrophic (HCM) and dilated (DCM), cause heart failure, but current treatments primarily manage symptoms.
• Patient-derived human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes offer a model to investigate genotype-specific disease mechanisms and drug responses.

Purpose of the Study:

• To investigate how MYBPC3 (HCM) and LMNA (DCM) mutations affect hiPSC-cardiomyocyte responses to mechanical stretch and a GATA4-targeted compound.
• To assess the utility of patient-derived hiPSC-cardiomyocytes for modeling cardiomyopathy pathophysiology and for drug discovery.

Main Methods:

• hiPSC-cardiomyocytes from healthy individuals and patients with MYBPC3 or LMNA mutations were subjected to cyclic mechanical stretch.
• Gene expression (qPCR) and protein levels (Western blotting) of hypertrophy-associated, mechanosensitive, and metabolism-related markers were analyzed.
• The effect of the GATA4-targeted compound 3i-1262 on cellular responses was evaluated.

Main Results:

• HCM and DCM cardiomyocytes showed distinct basal gene expression profiles compared to controls.
• Mechanical stretch differentially regulated specific genes (NPPB, MYH7, NPPA) in control, HCM, and DCM cardiomyocytes.
• The compound 3i-1262 demonstrated limited efficacy in modulating stretch-induced gene expression in patient-derived cells.

Conclusions:

• Cardiomyopathy-associated mutations significantly influence gene and protein expression and cellular responses to mechanical stimuli.
• Patient-derived hiPSC-cardiomyocytes are valuable tools for understanding cardiomyopathy pathogenesis and for identifying potential therapeutic targets.
• The study underscores the importance of genotype-specific approaches in cardiomyopathy research and drug development.