MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo

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Title: MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo
Authors: Schneider, M
Fiedler, L
Chapman, K
Xie, M
Maifosie, E
Jenkins, M
Golforoush, P
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, T
Harding, S
Low, CMR
Tralau-Stewart, C
Perrior, T
Schneider, MD
Item Type: Journal Article
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.
Issue Date: 4-Apr-2019
Date of Acceptance: 11-Feb-2019
ISSN: 1875-9777
Publisher: Elsevier (Cell Press)
Start Page: 579
End Page: 591.e12
Journal / Book Title: Cell Stem Cell
Volume: 24
Issue: 4
Copyright Statement: © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: SI/11/2/28875
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Cell Biology
cardiac muscle
drug discovery
signal transduction
Developmental Biology
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Online Publication Date: 2019-03-07
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine

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