A Contraction Stress Model of Hypertrophic Cardiomyopathy due to Sarcomere Mutations.
Calcium
/ metabolism
Cardiac Myosins
/ genetics
Cardiomyopathy, Hypertrophic
/ genetics
Carrier Proteins
/ genetics
Cell Line
Humans
Induced Pluripotent Stem Cells
/ cytology
Mutation
Myocardial Contraction
Myosin Heavy Chains
/ genetics
Oxidative Stress
Sarcomeres
/ genetics
Tumor Suppressor Protein p53
/ metabolism
cardiomyopathy
heart failure
hypertrophyp53 signaling
induced pluripotent stem cells
sarcomere function
tissue engineering
Journal
Stem cell reports
ISSN: 2213-6711
Titre abrégé: Stem Cell Reports
Pays: United States
ID NLM: 101611300
Informations de publication
Date de publication:
08 01 2019
08 01 2019
Historique:
received:
30
10
2018
revised:
18
11
2018
accepted:
19
11
2018
pubmed:
18
12
2018
medline:
28
2
2020
entrez:
18
12
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30554920
pii: S2213-6711(18)30483-1
doi: 10.1016/j.stemcr.2018.11.015
pmc: PMC6335568
pii:
doi:
Substances chimiques
Carrier Proteins
0
MYH7 protein, human
0
Tumor Suppressor Protein p53
0
myosin-binding protein C
0
Cardiac Myosins
EC 3.6.1.-
Myosin Heavy Chains
EC 3.6.4.1
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
71-83Subventions
Organisme : NHLBI NIH HHS
ID : K08 HL125807
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142787
Pays : United States
Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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