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Nature. 2017 Jan 12;541(7636):222-227. doi: 10.1038/nature20173. Epub 2016 Oct 31.

Hypoxia induces heart regeneration in adult mice.

Author information

1
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
2
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
3
Cardiovascular Division, King's College London BHF Centre of Research Excellence, Faculty of Medicine, James Black Centre, London SE5 9NU, UK.
4
Department of Cell Biology and Physiology, McAllister Heart Institute, the University of North Carolina, Chapel Hill, North Carolina 27599-7545, USA.
5
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
6
McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
7
Children's Medical Center Research Institute at UT Southwestern Medical Center, Dallas, Texas 75390, USA.
8
Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
9
Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
10
Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan.
11
Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

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.

PMID:
27798600
DOI:
10.1038/nature20173
[Indexed for MEDLINE]

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