dc.contributor.author | Fiedler, LR | |
dc.contributor.author | Chapman, K | |
dc.contributor.author | Xie, M | |
dc.contributor.author | Maifoshie, E | |
dc.contributor.author | Jenkins, M | |
dc.contributor.author | Golforoush, PA | |
dc.contributor.author | Bellahcene, M | |
dc.contributor.author | Noseda, M | |
dc.contributor.author | Faust, D | |
dc.contributor.author | Jarvis, A | |
dc.contributor.author | Newton, G | |
dc.contributor.author | Paiva, MA | |
dc.contributor.author | Harada, M | |
dc.contributor.author | Stuckey, DJ | |
dc.contributor.author | Song, W | |
dc.contributor.author | Habib, J | |
dc.contributor.author | Narasimhan, P | |
dc.contributor.author | Aqil, R | |
dc.contributor.author | Sanmugalingam, D | |
dc.contributor.author | Yan, R | |
dc.contributor.author | Pavanello, L | |
dc.contributor.author | Sano, M | |
dc.contributor.author | Wang, SC | |
dc.contributor.author | Sampson, RD | |
dc.contributor.author | Kanayaganam, S | |
dc.contributor.author | Taffet, GE | |
dc.contributor.author | Michael, LH | |
dc.contributor.author | Entman, ML | |
dc.contributor.author | Tan, T-H | |
dc.contributor.author | Harding, SE | |
dc.contributor.author | Low, CMR | |
dc.contributor.author | Tralau-Stewart, C | |
dc.contributor.author | Perrior, T | |
dc.contributor.author | Schneider, MD | |
dc.date.accessioned | 2020-08-13T15:37:42Z | |
dc.date.issued | 2019-04-04 | |
dc.identifier.citation | Cell stem cell, 2019, 24 (4), pp. 579 - 591.e12 | |
dc.identifier.issn | 1934-5909 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3961 | |
dc.identifier.eissn | 1875-9777 | |
dc.identifier.doi | 10.1016/j.stem.2019.01.013 | |
dc.description.abstract | 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 579 - 591.e12 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | CELL PRESS | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cells, Cultured | |
dc.subject | Myocytes, Cardiac | |
dc.subject | Animals | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Mice, Transgenic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Infarction | |
dc.subject | Hydrogen Peroxide | |
dc.subject | Doxorubicin | |
dc.subject | Protein-Serine-Threonine Kinases | |
dc.subject | Intracellular Signaling Peptides and Proteins | |
dc.subject | Cell Survival | |
dc.subject | Structure-Activity Relationship | |
dc.subject | Dose-Response Relationship, Drug | |
dc.subject | Female | |
dc.subject | Male | |
dc.subject | Induced Pluripotent Stem Cells | |
dc.title | MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-01-30 | |
rioxxterms.versionofrecord | 10.1016/j.stem.2019.01.013 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-04 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cell stem cell | |
pubs.issue | 4 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 24 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 3 | |
dc.contributor.icrauthor | Newton, Gary | |