MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo.
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Date
2019-04-04ICR Author
Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Cells, Cultured
Myocytes, Cardiac
Animals
Mice, Inbred C57BL
Mice, Transgenic
Humans
Mice
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
Research team
Medicinal Chemistry 3
Language
eng
Date accepted
2019-01-30
License start date
2019-04
Citation
Cell stem cell, 2019, 24 (4), pp. 579 - 591.e12
Publisher
CELL PRESS