Finding the Heart’s Regenerative Switch

Sci. Signal.  06 May 2014:
Vol. 7, Issue 324, pp. ec119
DOI: 10.1126/scisignal.2005448

Whereas the hearts of some vertebrate species have remarkable regenerative capacity, the mammalian heart can regenerate for only the first week after birth. Puente et al. found that the transition to an oxygen-rich postnatal environment induces DNA damage that stops proliferation in cardiomyocytes. Mitochondria in hearts from postnatal day 7 (P7) mice had increased DNA content, cristae density, and aerobic respiration enzyme abundance (all measures of mitochondrial function) compared with those in hearts of newborn mice. Aerobic respiration causes oxidative stress through the generation of reactive oxygen species (ROS), and ROS production was increased in hearts from P7 mice compared with those from newborns. Nuclear staining for the oxidative DNA lesion 8-oxo-7,8-dihydroguanine (8-oxoG), the number of 8-oxoG foci, and the abundance or activation of DNA damage response (DDR) proteins, including the kinase ATM, were increased in P7 compared with newborn hearts, indicating that ROS-induced DNA damage was increased after birth. Exposure to a hyperoxic environment from just before birth accelerated the increase in oxidative DNA damage and DDR protein activation after birth and decreased cardiomyocyte proliferation. In mice born in a mildly hypoxic environment, oxidative DNA damage and DDR protein activation were decreased, and heart weight and cardiomyocyte proliferation were increased, although cardiomyocyte size was decreased. Additionally, cardiomyocytes from hearts injected with hydrogen peroxide or from mice injected with ROS inducers had increased DNA damage and DDR activation, decreased mitosis, and were larger than controls, suggesting that ROS inhibits cardiomyocyte proliferation. ROS production, oxidative DNA damage, activation of the DDR, and cardiomyocyte size were decreased and cardiomyocyte proliferation was increased in mice treated with a ROS scavenger (NAC) or in mice expressing a mitochondrial-specific catalase only in cardiomyocytes. Furthermore, cardiomyocyte proliferation and cardiac function after ischemic injury at P21 was increased and fibrotic scar formation decreased in mice that received NAC injections from birth compared with those that had not. This finding identifies a key protective mechanism in newborn hearts, in which energy metabolism is promoted at the expense of cell proliferation, and may indicate therapeutic strategies for inducing regeneration in the adult heart.

B. N. Puente, W. Kimura, S. A. Muralidhar, J. Moon, J. F. Amatruda, K. L. Phelps, D. Grinsfelder, B. A. Rothermel, R. Chen, J. A. Garcia, C. X. Santos, S. Thet, E. Mori, M. T. Kinter, P. M. Rindler, S. Zacchigna, S. Mukherjee, D. J. Chen, A. I. Mahmoud, M. Giacca, P. S. Rabinovitch, A. Aroumougame, A. M. Shah, L. I. Szweda, H. A. Sadek. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157, 565–579 (2014). [PubMed]