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

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

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: m.d.schneider@imperial.ac.uk.
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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