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

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

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

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MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo.pdf (4.49 MB)

ICR Authors

Newton, Gary

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

Document Type

Journal Article

Date

2019-04-04

Date Accepted

2019-01-30

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.

Citation

Cell stem cell, 2019, 24 (4), pp. 579 - 591.e12

DOI

10.1016/j.stem.2019.01.013

URI

https://repository.icr.ac.uk/handle/internal/3961

Rights

https://creativecommons.org/licenses/by/4.0

Publisher

CELL PRESS

ISSN

1934-5909

eISSN

1875-9777

Collections

Cancer Therapeutics

Research Team

Medicinal Chemistry 3

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