| Title: |
MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo. |
| Authors: |
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; Narasimhan, P; Aqil, R; Sanmugalingam, D; Yan, R; Pavanello, L; Sano, M; Wang, SC; Sampson, RD; Kanayaganam, S; Taffet, GE; Michael, LH; Entman, ML; Tan, T-H; Harding, SE; Low, CMR; Tralau-Stewart, C; Perrior, T; Schneider, MD |
| Contributors: |
Newton, Gary |
| Publisher Information: |
CELL PRESS |
| Publication Year: |
2020 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Cells; Cultured; Myocytes; Cardiac; Animals; Mice; Inbred C57BL; Transgenic; Humans; Infarction; Hydrogen Peroxide; Doxorubicin; Protein-Serine-Threonine Kinases; Intracellular Signaling Peptides and Proteins; Cell Survival; Structure-Activity Relationship; Dose-Response Relationship; Drug; Female; Male; Induced Pluripotent Stem Cells |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print-Electronic; 591.e12; application/pdf |
| Language: |
English |
| ISSN: |
1875-9777; 1934-5909 |
| Relation: |
Cell stem cell, 2019, 24 (4), pp. 579 - 591.e12; https://repository.icr.ac.uk/handle/internal/3961 |
| DOI: |
10.1016/j.stem.2019.01.013 |
| Availability: |
https://doi.org/10.1016/j.stem.2019.01.013; https://repository.icr.ac.uk/handle/internal/3961 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.742124F3 |
| Database: |
BASE |