MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo.
Animals
Cell Survival
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Doxorubicin
/ pharmacology
Female
Humans
Hydrogen Peroxide
/ pharmacology
Induced Pluripotent Stem Cells
/ cytology
Infarction
/ drug therapy
Intracellular Signaling Peptides and Proteins
/ antagonists & inhibitors
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocytes, Cardiac
/ cytology
Protein Serine-Threonine Kinases
/ antagonists & inhibitors
Structure-Activity Relationship
apoptosis
cardiac muscle
drug discovery
heart
signal transduction
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
04 04 2019
04 04 2019
Historique:
received:
10
11
2017
revised:
24
12
2018
accepted:
30
01
2019
pubmed:
12
3
2019
medline:
19
5
2020
entrez:
12
3
2019
Statut:
ppublish
Résumé
Heart disease is a paramount cause of global death and disability. Although cardiomyocyte death plays a causal role and its suppression would be logical, no clinical counter-measures target the responsible intracellular pathways. Therapeutic progress has been hampered by lack of preclinical human validation. Mitogen-activated protein kinase kinase kinase kinase-4 (MAP4K4) is activated in failing human hearts and relevant rodent models. Using human induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) and MAP4K4 gene silencing, we demonstrate that death induced by oxidative stress requires MAP4K4. Consequently, we devised a small-molecule inhibitor, DMX-5804, that rescues cell survival, mitochondrial function, and calcium cycling in hiPSC-CMs. As proof of principle that drug discovery in hiPSC-CMs may predict efficacy in vivo, DMX-5804 reduces ischemia-reperfusion injury in mice by more than 50%. We implicate MAP4K4 as a well-posed target toward suppressing human cardiac cell death and highlight the utility of hiPSC-CMs in drug discovery to enhance cardiomyocyte survival.
Identifiants
pubmed: 30853557
pii: S1934-5909(19)30013-X
doi: 10.1016/j.stem.2019.01.013
pmc: PMC6458995
pii:
doi:
Substances chimiques
Intracellular Signaling Peptides and Proteins
0
Doxorubicin
80168379AG
Hydrogen Peroxide
BBX060AN9V
MAP4K4 protein, human
EC 2.7.1.11
Protein Serine-Threonine Kinases
EC 2.7.11.1
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
579-591.e12Subventions
Organisme : British Heart Foundation
ID : SI/11/2/28875
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 205256/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0901467
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RE/08/002
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT10638
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC PC 12015
Pays : United Kingdom
Organisme : Wellcome Trust
ID : WT205256
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/08/007
Pays : United Kingdom
Organisme : European Research Council
ID : 233158
Pays : International
Organisme : British Heart Foundation
ID : CH/08/002/29257
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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