期刊
CELL STEM CELL
卷 24, 期 4, 页码 579-+出版社
CELL PRESS
DOI: 10.1016/j.stem.2019.01.013
关键词
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资金
- BHF [CH/08/002/29257, RE/08/002, RG/08/007, SI/11/2/28875]
- European Commission [223372]
- European Research Council [233158]
- MRC-BHF Cardiovascular Stem Cell Research Strategic Development Grant [G0901467]
- MRC-Imperial Confidence in Concept Fund [MC PC 12015]
- NIH [R01 HL52555]
- Wellcome Trust [WT10638, WT205256]
- MRC [G0901467] Funding Source: UKRI
- European Research Council (ERC) [233158] Funding Source: European Research Council (ERC)
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.
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