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

  • Cell Stem Cell. 2019 Apr 4;24(4):579-591.e12. doi: 10.1016/j.stem.2019.01.013.
Lorna R Fiedler  1 ,  Kathryn Chapman  2 ,  Min Xie  3 ,  Evie Maifoshie  1 ,  Micaela Jenkins  1 ,  Pelin Arabacilar Golforoush  1 ,  Mohamed Bellahcene  1 ,  Michela Noseda  1 ,  Dörte Faust  1 ,  Ashley Jarvis  4 ,  Gary Newton  4 ,  Marta Abreu Paiva  1 ,  Mutsuo Harada  1 ,  Daniel J Stuckey  1 ,  Weihua Song  1 ,  Josef Habib  1 ,  Priyanka Narasimhan  4 ,  Rehan Aqil  4 ,  Devika Sanmugalingam  4 ,  Robert Yan  4 ,  Lorenzo Pavanello  4 ,  Motoaki Sano  3 ,  Sam C Wang  3 ,  Robert D Sampson  1 ,  Sunthar Kanayaganam  1 ,  George E Taffet  3 ,  Lloyd H Michael  3 ,  Mark L Entman  3 ,  Tse-Hua Tan  5 ,  Sian E Harding  1 ,  Caroline M R Low  6 ,  Catherine Tralau-Stewart  6 ,  Trevor Perrior  4 ,  Michael D Schneider  7
Affiliations
  • 1. British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
  • 2. Drug Discovery Centre, Department of Medicine, Imperial College London, London SW7 2AZ, UK; Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK; Domainex, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK.
  • 3. Michael E. DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
  • 4. Domainex, Chesterford Research Park, Little Chesterford, Saffron Walden, Essex CB10 1XL, UK.
  • 5. Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan; Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 6. Drug Discovery Centre, Department of Medicine, Imperial College London, London SW7 2AZ, UK.
  • 7. British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, London W12 0NN, UK; Michael E. DeBakey Heart Center, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
PMID: 30853557 DOI: 10.1016/j.stem.2019.01.013
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.

Keywords
apoptosis; cardiac muscle; drug discovery; heart; signal transduction.
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