Document Type

Article

Publication Date

1-8-2019

Keywords

JGM

JAX Source

Stem Cell Reports 2019 Jan 8; 12(1):71-83

PMID

30554920

DOI

https://doi.org/10.1016/j.stemcr.2018.11.015

Grant

HL125807, HL142787

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 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.

Comments

We thank Anthony Carcio for contributions to the flow cytometry experiments, and Qianru Yu for expertise in confocal microscopy.

This open access article is licensed under a Creative Commons Attribution 4.0 International License

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