Cardiomyocyte apoptosis contributes to contractile dysfunction in stem cell model of MYH7 E848G hypertrophic cardiomyopathy
Cardiomyocyte apoptosis contributes to contractile dysfunction in stem cell model of MYH7 E848G hypertrophic cardiomyopathy
Abstract Missense mutations in myosin heavy chain 7 (MYH7) are a common cause of hyper-trophic cardiomyopathy (HCM), but the molecular mechanisms underlying MYH7-based HCM remain unclear. In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenic MYH7 missense 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 in MYH7 E848G HCM patients. Interestingly, MYH7E848G/+ cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicating MYH7E848G/+ cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis plays an important role in the MYH7E848G/+ HCM phenotype in vitro and that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction.
Murry Charles E.、Yang Kai-Chun、Sniadecki Nathan、Chao Leslie S-L.、Chien Wei-Ming、Loiben Alexander M.、Goldstein Alex、Weber Gerhard、Friedman Clayton E.
Institute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of Washington||Department of Bioengineering, University of Washington||Department of Lab Medicine and Pathology, University of WashingtonInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of Washington||Cardiology/Hospital Specialty Medicine, VA Puget Sound HCSInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of Washington||Department of Mechanical Engineering, University of Washington||Department of Bioengineering, University of Washington||Department of Lab Medicine and Pathology, University of WashingtonInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of WashingtonInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of Washington||Cardiology/Hospital Specialty Medicine, VA Puget Sound HCSInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of WashingtonInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of Washington||Department of Mechanical Engineering, University of Washington||Department of Lab Medicine and Pathology, University of WashingtonDepartment of Medicine/Cardiology, University of WashingtonInstitute for Stem Cell and Regenerative Medicine, University of Washington, School of Medicine||Center for Cardiovascular Biology, University of Washington||Department of Medicine/Cardiology, University of Washington
基础医学细胞生物学分子生物学
Hypertrophic cardiomyopathydilated cardiomyopathyMYH7p53engineered heart tissueapoptosiscontractile dysfunctioninduced pluripotent stem cells
Murry Charles E.,Yang Kai-Chun,Sniadecki Nathan,Chao Leslie S-L.,Chien Wei-Ming,Loiben Alexander M.,Goldstein Alex,Weber Gerhard,Friedman Clayton E..Cardiomyocyte apoptosis contributes to contractile dysfunction in stem cell model of MYH7 E848G hypertrophic cardiomyopathy[EB/OL].(2025-03-28)[2025-04-27].https://www.biorxiv.org/content/10.1101/2023.01.24.525458.点此复制
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