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Hypoxia induces heart regeneration in adult mice

Item Type:Article
Title:Hypoxia induces heart regeneration in adult mice
Creators Name:Nakada, Y. and Canseco, D.C. and Thet, S. and Abdisalaam, S. and Asaithamby, A. and Santos, C.X. and Shah, A.M. and Zhang, Hua and Faber, J.E. and Kinter, M.T. and Szweda, L.I. and Xing, C. and Hu, Z. and Deberardinis, R.J. and Schiattarella, G. and Hill, J.A. and Oz, O. and Lu, Z. and Zhang, C.C. and Kimura, W. and Sadek, H.A.
Abstract:The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.
Keywords:Cardiomyopathies, Cell Proliferation, Cell Respiration, Cardiac Myocytes, DNA Damage, Heart, Hypoxia, Inbred C57BL Mice, Left Ventricular Function, Mitochondria, Mitosis, Myocardial Infarction, Myocardium, Reactive Oxygen Species, Regeneration, Regenerative Medicine, Animals, Mice
Publisher:Nature Publishing Group
Page Range:222-227
Date:12 January 2017
Official Publication:https://doi.org/10.1038/nature20173
PubMed:View item in PubMed

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