Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Arrhythmias, Cardiac
/ complications
Azoles
/ pharmacology
Calcium
/ metabolism
Cardiomyopathies
/ etiology
Cell Line
Electrophysiological Phenomena
/ drug effects
Humans
Induced Pluripotent Stem Cells
/ drug effects
Iron
/ metabolism
Iron Overload
/ complications
Isoindoles
Kinetics
Mitochondria
/ drug effects
Models, Biological
Myocardial Contraction
/ drug effects
Myocytes, Cardiac
/ pathology
Organoselenium Compounds
/ pharmacology
Oxidative Stress
/ drug effects
Phenotype
Time Factors
Transcription Factors
/ antagonists & inhibitors
Transcriptome
/ drug effects
DMT1
calcium handling
cardiac spheroids
cardiomyocytes
ebselen
iPSC
iron overload cardiomyopathy
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
14 07 2020
14 07 2020
Historique:
received:
05
12
2019
revised:
20
04
2020
accepted:
17
06
2020
entrez:
16
7
2020
pubmed:
16
7
2020
medline:
30
4
2021
Statut:
ppublish
Résumé
Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we model IOC and screen for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions. We identify that ebselen, a selective divalent metal transporter 1 (DMT1) inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload.
Identifiants
pubmed: 32668256
pii: S2211-1247(20)30867-6
doi: 10.1016/j.celrep.2020.107886
pmc: PMC7553857
mid: NIHMS1631824
pii:
doi:
Substances chimiques
Azoles
0
DMRT1 protein
0
Isoindoles
0
Organoselenium Compounds
0
Transcription Factors
0
ebselen
40X2P7DPGH
Iron
E1UOL152H7
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107886Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL113006
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL141851
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL123968
Pays : United States
Organisme : NHLBI NIH HHS
ID : K99 HL150216
Pays : United States
Organisme : NHLBI NIH HHS
ID : K01 HL135455
Pays : United States
Organisme : NHLBI NIH HHS
ID : R25 HL147666
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130020
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL141084
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests J.C.W. is a cofounder of Khloris Biosciences but has no competing interests, as the work presented here is completely independent.
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