| Popis: |
Missense mutations in myosin heavy chain 7 (MYH7) are a common cause of hyper-trophic cardiomyopathy (HCM), but the molecular mechanisms underlyingMYH7-based HCM remain unclear. In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenicMYH7missense variant, E848G, which is associated with left ventricular hypertrophy and adultonset systolic dysfunction.MYH7E848G/+increased cardiomyocyte size and reduced the maximum twitch forces of engineered heart tissue, consistent with the systolic dysfunction inMYH7E848G HCM patients. Interestingly,MYH7E848G/+cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation ofTP53did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicatingMYH7E848G/+cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis plays an important role in theMYH7E848G/+HCM phenotypein vitroand that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction. |
