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Cell. 2014 Apr 24;157(3):565-79. doi: 10.1016/j.cell.2014.03.032.

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

Author information

  • 1Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 6Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 8Cardiovascular Division, King's College London BHF Centre of Research Excellence, School of Medicine, James Black Centre, London SE5 9NU, UK.
  • 9Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 10Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
  • 11Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy.
  • 12Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02115, USA.
  • 13Department of Pathology, University of Washington, Seattle, WA 98195, USA.
  • 14Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hesham.sadek@utsouthwestern.edu.

Erratum in

  • Cell. 2014 May 22;157(5):1243.

Abstract

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24766806
[PubMed - indexed for MEDLINE]
PMCID:
PMC4104514
Free PMC Article
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