Thick-filament sarcomere mutations in iPSC-derived cardiomyocytes resulted in hypercontractility, prolonged relaxation kinetics, and p53 activation, oxidative stress, and cytotoxicity.
Hypercontractility is a direct consequence of thick-filament mutations in hypertrophic cardiomyopathy, and the p53 pathway represents a molecular marker of contraction stress and a potential therapeutic target.
Thick-filament sarcomere mutations are a common cause of hypertrophic cardiomyopathy (HCM), a disorder of heart muscle thickening associated with sudden cardiac death and heart failure, with unclear mechanisms. We engineered four isogenic induced pluripotent stem cell (iPSC) models of β-myosin heavy chain and myosin-binding protein C3 mutations, and studied iPSC-derived cardiomyocytes in cardiac microtissue assays that resemble cardiac architecture and biomechanics. All HCM mutations resulted in hypercontractility with prolonged relaxation kinetics in proportion to mutation pathogenicity, but not changes in calcium handling. RNA sequencing and expression studies of HCM models identified p53 activation, oxidative stress, and cytotoxicity induced by metabolic stress that can be reversed by p53 genetic ablation. Our findings implicate hypercontractility as a direct consequence of thick-filament mutations, irrespective of mutation localization, and the p53 pathway as a molecular marker of contraction stress and candidate therapeutic target for HCM patients.
Cohn et al. (Thu,) conducted a other in Hypertrophic cardiomyopathy. iPSC models of β-myosin heavy chain and myosin-binding protein C3 mutations vs. Isogenic controls was evaluated on Hypercontractility, relaxation kinetics, and molecular markers of contraction stress. Thick-filament sarcomere mutations in iPSC-derived cardiomyocytes resulted in hypercontractility, prolonged relaxation kinetics, and p53 activation, oxidative stress, and cytotoxicity.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: