title: Hypoxia induces heart regeneration in adult mice.
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.
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Yuji
authors: Y
authors: Nakada
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Diana C
authors: DC
authors: Canseco
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: SuWannee
authors: S
authors: Thet
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Salim
authors: S
authors: Abdisalaam
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Aroumougame
authors: A
authors: Asaithamby
authors: Cardiovascular Division, King's College London BHF Centre of Research Excellence, Faculty of Medicine, James Black Centre, London SE5 9NU, UK.
authors: Celio X
authors: CX
authors: Santos
authors: Cardiovascular Division, King's College London BHF Centre of Research Excellence, Faculty of Medicine, James Black Centre, London SE5 9NU, UK.
authors: Ajay M
authors: AM
authors: Shah
authors: Department of Cell Biology and Physiology, McAllister Heart Institute, the University of North Carolina, Chapel Hill, North Carolina 27599-7545, USA.
authors: Hua
authors: H
authors: Zhang
authors: Department of Cell Biology and Physiology, McAllister Heart Institute, the University of North Carolina, Chapel Hill, North Carolina 27599-7545, USA.
authors: James E
authors: JE
authors: Faber
authors: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
authors: Michael T
authors: MT
authors: Kinter
authors: Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
authors: Luke I
authors: LI
authors: Szweda
authors: McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Chao
authors: C
authors: Xing
authors: Children's Medical Center Research Institute at UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Zeping
authors: Z
authors: Hu
authors: Children's Medical Center Research Institute at UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Ralph J
authors: RJ
authors: Deberardinis
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Gabriele
authors: G
authors: Schiattarella
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Joseph A
authors: JA
authors: Hill
authors: Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Orhan
authors: O
authors: Oz
authors: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Zhigang
authors: Z
authors: Lu
authors: Department of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Cheng Cheng
authors: CC
authors: Zhang
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan.
authors: Wataru
authors: W
authors: Kimura
authors: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.|Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors: Hesham A
authors: HA
authors: Sadek
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D019069:Cell Respiration; D004249:DNA Damage; D006321:Heart / Q000254:growth & development*; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D008938:Mitosis; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012038:Regeneration; D044968:Regenerative Medicine / Q000379:methods*; D016277:Ventricular Function, Left
chemical_list: D017382:Reactive Oxygen Species