A Contraction Stress Model of Hypertrophic Cardiomyopathy due to Sarcomere Mutations.
Stem Cell Reports
; 12(1): 71-83, 2019 01 08.
Article
en En
| MEDLINE
| ID: mdl-30554920
ABSTRACT
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 ß-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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Sarcómeros
/
Cardiomiopatía Hipertrófica
/
Mutación
/
Contracción Miocárdica
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Stem Cell Reports
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos