MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo
| Autor: | Priyanka Narasimhan, Dörte Faust, Devika Sanmugalingam, Motoaki Sano, Lorna R. Fiedler, Caroline M. R. Low, Gary Newton, Michela Noseda, Michael D. Schneider, Weihua Song, Marta Abreu Paiva, Daniel J. Stuckey, Sam C. Wang, Rehan Aqil, Tse-Hua Tan, Trevor Perrior, Evie Maifoshie, Lorenzo Pavanello, Micaela Jenkins, George E. Taffet, Mark L. Entman, Sunthar Kanayaganam, Ashley Jarvis, Min Xie, Catherine Tralau-Stewart, Pelin Arabacilar Golforoush, Sian E. Harding, Lloyd H. Michael, Mohamed Bellahcene, Robert D. Sampson, Robert Yan, Mutsuo Harada, Kathryn Chapman, Josef Habib |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Cell Survival Induced Pluripotent Stem Cells Cell Mice Transgenic Protein Serine-Threonine Kinases Biology Article Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine In vivo Genetics medicine Animals Humans Myocytes Cardiac Cells Cultured 030304 developmental biology 0303 health sciences Dose-Response Relationship Drug Intracellular Signaling Peptides and Proteins Hydrogen Peroxide Cell Biology Infarct size 3. Good health Cell biology Mice Inbred C57BL medicine.anatomical_structure Doxorubicin Infarction Molecular Medicine Female Stem cell 030217 neurology & neurosurgery |
| Zdroj: | Cell Stem Cell |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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