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.

Cardiac Insulin Signaling Regulates Glycolysis Through Phosphofructokinase 2 Content and Activity

“…Heart samples were prepared on the basis of our standard targeted proteomics approach 19, 20, 21, 22. Whole heart homogenates were used for the analysis.…”

Evolution of peroxisomes illustrates symbiogenesis

“…A good example can be found in cardiomyocytes, which preferentially indeed use long-chain FAs as their energy source and contain large amounts of mitochondria [13]. The large majority of these cells is not able to regenerate, but a small population of "hypoxic" cardiomyocytes (those that have stabilized the hypoxia-inducible factor 1 alpha subunit) can contribute to new cardiomyocyte formation for ongoing repair of the adult heart [14,15]. There is a parallel here with the elusive neural stem cell that allows neuronal regeneration [16].…”

Concise Review: Mending a Broken Heart: The Evolution of Biological Therapeutics

“…Perhaps one of the most promising developments in the field of the regenerative cardiology is the emerging notion of using pre-existing cardiomyocytes as the source for cardiomyocyte replacement to maintain normal myocardial homeostasis as well as after myocardial injury [77][78][79][80]. The stimulation of proliferation of pre-existing cardiomyocytes could provide new avenues for future therapeutic strategies to regenerate the heart.…”