Uncompensated mitochondrial oxidative stress underlies heart failure in an iPSC-derived model of congenital heart disease.
TUDCA
antioxidant response
congenital heart disease
endoplasmic reticulum stress
heart failure
hypoplastic left heart syndrome
i
induced pluripotent stem-cell-derived cardiomyocytes
mitochondrial permeability transition pore
oxidative stress
sildenafil
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
05 05 2022
05 05 2022
Historique:
received:
26
04
2021
revised:
19
11
2021
accepted:
08
03
2022
pubmed:
9
4
2022
medline:
11
5
2022
entrez:
8
4
2022
Statut:
ppublish
Résumé
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease with 30% mortality from heart failure (HF) in the first year of life, but the cause of early HF remains unknown. Induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CM) from patients with HLHS showed that early HF is associated with increased apoptosis, mitochondrial respiration defects, and redox stress from abnormal mitochondrial permeability transition pore (mPTP) opening and failed antioxidant response. In contrast, iPSC-CM from patients without early HF showed normal respiration with elevated antioxidant response. Single-cell transcriptomics confirmed that early HF is associated with mitochondrial dysfunction accompanied with endoplasmic reticulum (ER) stress. These findings indicate that uncompensated oxidative stress underlies early HF in HLHS. Importantly, mitochondrial respiration defects, oxidative stress, and apoptosis were rescued by treatment with sildenafil to inhibit mPTP opening or TUDCA to suppress ER stress. Together these findings point to the potential use of patient iPSC-CM for modeling clinical heart failure and the development of therapeutics.
Identifiants
pubmed: 35395180
pii: S1934-5909(22)00101-1
doi: 10.1016/j.stem.2022.03.003
pmc: PMC9302582
mid: NIHMS1796868
pii:
doi:
Substances chimiques
Antioxidants
0
Mitochondrial Permeability Transition Pore
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
840-855.e7Subventions
Organisme : NHLBI NIH HHS
ID : U01 HL148861
Pays : United States
Organisme : NHLBI NIH HHS
ID : U24 HL148865
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL142788
Pays : United States
Organisme : NHLBI NIH HHS
ID : U01 HL122700
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132024
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144776
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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