MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo

• Published in: Cell stem cell 2019-04, Vol.24 (4), p.579-591.e12
• Main Authors: Fiedler, Lorna R., Chapman, Kathryn, Xie, Min, Maifoshie, Evie, Jenkins, Micaela, Golforoush, Pelin Arabacilar, Bellahcene, Mohamed, Noseda, Michela, Faust, Dörte, Jarvis, Ashley, Newton, Gary, Paiva, Marta Abreu, Harada, Mutsuo, Stuckey, Daniel J., Song, Weihua, Habib, Josef, Narasimhan, Priyanka, Aqil, Rehan, Sanmugalingam, Devika, Yan, Robert, Pavanello, Lorenzo, Sano, Motoaki, Wang, Sam C., Sampson, Robert D., Kanayaganam, Sunthar, Taffet, George E., Michael, Lloyd H., Entman, Mark L., Tan, Tse-Hua, Harding, Sian E., Low, Caroline M.R., Tralau-Stewart, Catherine, Perrior, Trevor, Schneider, Michael D.
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; cardiac muscle; Cell Survival - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; drug discovery; Female; heart; Humans; Hydrogen Peroxide - pharmacology; Induced Pluripotent Stem Cells - cytology; Infarction - drug therapy; Infarction - metabolism; Infarction - pathology; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; signal transduction; Structure-Activity Relationship
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2019.01.013

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. [Display omitted] •Human iPSC-cardiomyocytes were used for MAP4K4 target validation and drug discovery•MAP4K4 shRNA protects hiPSC-cardiomyocytes from lethal oxidative stress•MAP4K4 inhibitors promote hiPSC-cardiomyocyte survival and function•MAP4K4 inhibition markedly reduces cardiac ischemia-reperfusion injury in mice Using human iPSC-derived cardiomyocytes to enhance cardiac drug discovery, Fiedler et al. performed MAP4K4 target validation by gene silencing in this human model. MAP4K4 inhibitors augment human cardiomyocyte viability and function in 2D culture and 3D engineered heart tissue. An exemplar successfully reduces infarct size in proof-of-principle studies in mice.