Hypoxia induces heart regeneration in adult mice

A pathway triggered by chronic severe hypoxia boosts regeneration of injured hearts in adult mice. Hypoxia pathway linked to heart regeneration Hesham Sadek and colleagues show that a pathway triggered by chronic severe hypoxia boosts the regeneration of injured hearts in adult mice. Mice subjected to myocardial infarction that are placed in a hypoxic environment for a prolonged period make new cardiomyocytes, and recover heart function through a mechanism involving a reduction of reactive oxygen species concentration and cardiomyocyte cell cycle re-entry. Prolonged severe hypoxia is not a viable therapeutic strategy for use in humans, but targeting this pathway can induce myocardial regeneration. 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 1 , and the adult heart is capable of modest self-renewal 2 , 3 . 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 4 , 5 . 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.