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dc.contributor.authorFiedler, LR
dc.contributor.authorChapman, K
dc.contributor.authorXie, M
dc.contributor.authorMaifoshie, E
dc.contributor.authorJenkins, M
dc.contributor.authorGolforoush, PA
dc.contributor.authorBellahcene, M
dc.contributor.authorNoseda, M
dc.contributor.authorFaust, D
dc.contributor.authorJarvis, A
dc.contributor.authorNewton, G
dc.contributor.authorPaiva, MA
dc.contributor.authorHarada, M
dc.contributor.authorStuckey, DJ
dc.contributor.authorSong, W
dc.contributor.authorHabib, J
dc.contributor.authorNarasimhan, P
dc.contributor.authorAqil, R
dc.contributor.authorSanmugalingam, D
dc.contributor.authorYan, R
dc.contributor.authorPavanello, L
dc.contributor.authorSano, M
dc.contributor.authorWang, SC
dc.contributor.authorSampson, RD
dc.contributor.authorKanayaganam, S
dc.contributor.authorTaffet, GE
dc.contributor.authorMichael, LH
dc.contributor.authorEntman, ML
dc.contributor.authorTan, T-H
dc.contributor.authorHarding, SE
dc.contributor.authorLow, CMR
dc.contributor.authorTralau-Stewart, C
dc.contributor.authorPerrior, T
dc.contributor.authorSchneider, MD
dc.date.accessioned2020-08-13T15:37:42Z
dc.date.issued2019-04
dc.identifier.citationCell stem cell, 2019, 24 (4), pp. 579 - 591.e12
dc.identifier.issn1934-5909
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3961
dc.identifier.eissn1875-9777
dc.identifier.doi10.1016/j.stem.2019.01.013
dc.description.abstractHeart 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.
dc.formatPrint-Electronic
dc.format.extent579 - 591.e12
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCells, Cultured
dc.subjectMyocytes, Cardiac
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectMice, Transgenic
dc.subjectHumans
dc.subjectMice
dc.subjectInfarction
dc.subjectHydrogen Peroxide
dc.subjectDoxorubicin
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectIntracellular Signaling Peptides and Proteins
dc.subjectCell Survival
dc.subjectStructure-Activity Relationship
dc.subjectDose-Response Relationship, Drug
dc.subjectFemale
dc.subjectMale
dc.subjectInduced Pluripotent Stem Cells
dc.titleMAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo.
dc.typeJournal Article
dcterms.dateAccepted2019-01-30
rioxxterms.versionofrecord10.1016/j.stem.2019.01.013
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2019-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCell stem cell
pubs.issue4
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 3
pubs.publication-statusPublished
pubs.volume24
pubs.embargo.termsNot known
icr.researchteamMedicinal Chemistry 3en_US
dc.contributor.icrauthorNewton, Garyen


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