The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response

Bao N. Puente, Wataru Kimura, Shalini A. Muralidhar, Jesung Moon, James F. Amatruda, Kate L. Phelps, David Grinsfelder, Beverly A. Rothermel, Rui Chen, Joseph A. Garcia, Celio X. Santos, Suwannee Thet, Eiichiro Mori, Michael T. Kinter, Paul M. Rindler, Serena Zacchigna, Shibani Mukherjee, David J. Chen, Ahmed I. Mahmoud, Mauro GiaccaPeter S. Rabinovitch, Asaithamby Aroumougame, Ajay M. Shah, Luke I. Szweda, Hesham A. Sadek

Research output: Contribution to journalArticlepeer-review

498 Scopus citations


The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary postnatal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen-rich postnatal environment is the upstream signal that results in cell-cycle arrest of cardiomyocytes. Here, we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, whereas hyperoxemia and ROS generators shorten it. These findings uncover a protective mechanism that mediates cardiomyocyte cell-cycle arrest in exchange for utilization of oxygen-dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be an important component of cardiomyocyte proliferation-based therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)565-579
Number of pages15
Issue number3
StatePublished - Apr 24 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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