Imperial College London

ProfessorMichaelSchneider

Faculty of MedicineNational Heart & Lung Institute

Chair in Cardiology
 
 
 
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Contact

 

+44 (0)013 34621727m.d.schneider Website

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Schneider:2019:10.1016/j.stem.2019.01.013,
author = {Schneider, M and Fiedler, L and Chapman, K and Xie, M and Maifosie, E and Jenkins, M and Golforoush, P and Bellahcene, M and Noseda, M and Faust, D and Jarvis, A and Newton, G and Paiva, MA and Harada, M and Stuckey, DJ and Song, W and Habib, J and Narasimham, P and Aqil, R and Sanmugalingam, D and Yan, R and Pavanello, L and Sano, M and Wang, SC and Sampson, RD and Kanayaganam, S and Taffet, GE and Michael, LH and Entman, ML and Tan, T and Harding, S and Low, CMR and Tralau-Stewart, C and Perrior, T and Schneider, MD},
doi = {10.1016/j.stem.2019.01.013},
journal = {Cell Stem Cell},
pages = {579--591.e12},
title = {MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo},
url = {http://dx.doi.org/10.1016/j.stem.2019.01.013},
volume = {24},
year = {2019}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Schneider,M
AU - Fiedler,L
AU - Chapman,K
AU - Xie,M
AU - Maifosie,E
AU - Jenkins,M
AU - Golforoush,P
AU - Bellahcene,M
AU - Noseda,M
AU - Faust,D
AU - Jarvis,A
AU - Newton,G
AU - Paiva,MA
AU - Harada,M
AU - Stuckey,DJ
AU - Song,W
AU - Habib,J
AU - Narasimham,P
AU - Aqil,R
AU - Sanmugalingam,D
AU - Yan,R
AU - Pavanello,L
AU - Sano,M
AU - Wang,SC
AU - Sampson,RD
AU - Kanayaganam,S
AU - Taffet,GE
AU - Michael,LH
AU - Entman,ML
AU - Tan,T
AU - Harding,S
AU - Low,CMR
AU - Tralau-Stewart,C
AU - Perrior,T
AU - Schneider,MD
DO - 10.1016/j.stem.2019.01.013
EP - 591
PY - 2019///
SN - 1875-9777
SP - 579
TI - MAP4K4 inhibition promotes survival of human stem cell derived cardiomyocyte and reduces infarct size in vivo
T2 - Cell Stem Cell
UR - http://dx.doi.org/10.1016/j.stem.2019.01.013
UR - http://hdl.handle.net/10044/1/67491
VL - 24
ER -