TY - JOUR
T1 - Hypoxia induces heart regeneration in adult mice
AU - Nakada, Yuji
AU - Canseco, Diana C.
AU - Thet, Suwannee
AU - Abdisalaam, Salim
AU - Asaithamby, Aroumougame
AU - Xavier Da Costa Dos Santos, Celio Santos
AU - Shah, Ajay M.
AU - Zhang, Hua
AU - Faber, James E.
AU - Kinter, Michael T.
AU - Szweda, Luke I.
AU - Xing, Chao
AU - Hu, Zeping
AU - Deberardinis, Ralph J.
AU - Schiattarella, Gabriele
AU - Hill, Joseph A.
AU - Oz, Orhan
AU - Lu, Zhigang
AU - Zhang, Cheng Cheng
AU - Kimura, Wataru
AU - Sadek, Hesham A.
PY - 2017/1/12
Y1 - 2017/1/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014090889&partnerID=8YFLogxK
U2 - 10.1038/nature20173
DO - 10.1038/nature20173
M3 - Article
C2 - 27798600
AN - SCOPUS:85014090889
SN - 0028-0836
VL - 541
SP - 222
EP - 227
JO - NATURE
JF - NATURE
IS - 7636
ER -