國家衛生研究院 NHRI:Item 3990099045/11780
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    题名: MAP4K4 inhibition promotes survival of human stem cell-derived cardiomyocytes and reduces infarct size in vivo
    作者: Fiedler, LR;Chapman, K;Xie, M;Maifoshie, E;Jenkins, M;Golforoush, PA;Bellahcene, M;Noseda, M;Faust, D;Jarvis, A;Newton, G;Paiva, MA;Harada, M;Stuckey, DJ;Song, W;Habib, J;Narasimham, P;Aqil, R;Sanmugalingam, D;Yan, R;Pavanello, L;Sano, M;Wang, SC;Sampson, RD;Kanayaganam, S;Taffet, GE;Michael, LH;Entman, ML;Tan, TH;Harding, SE;Low, CMR;Tralau-Stewart, C;Perrior, T;Schneider, MD
    贡献者: Immunology Research Center
    摘要: 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.
    日期: 2019-04
    關聯: Cell Stem Cell. 2019 Apr;24(4):579-591.e12.
    Link to: http://dx.doi.org/10.1016/j.stem.2019.01.013
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1934-5909&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000463353000013
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85063026492
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