The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response.
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.
Department 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.
Bao N
BN
Puente
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Wataru
W
Kimura
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shalini A
SA
Muralidhar
Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Jesung
J
Moon
Department 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.
James F
JF
Amatruda
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Kate L
KL
Phelps
Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
David
D
Grinsfelder
Department 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.
Beverly A
BA
Rothermel
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Rui
R
Chen
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Joseph A
JA
Garcia
Cardiovascular Division, King's College London BHF Centre of Research Excellence, School of Medicine, James Black Centre, London SE5 9NU, UK.
Celio X
CX
Santos
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
SuWannee
S
Thet
Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Eiichiro
E
Mori
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Michael T
MT
Kinter
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Paul M
PM
Rindler
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy.
Serena
S
Zacchigna
Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Shibani
S
Mukherjee
Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
David J
DJ
Chen
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02115, USA.
Ahmed I
AI
Mahmoud
Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy.
Mauro
M
Giacca
Department of Pathology, University of Washington, Seattle, WA 98195, USA.
Peter S
PS
Rabinovitch
Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Asaithamby
A
Aroumougame
Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Ajay M
AM
Shah
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Luke I
LI
Szweda
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hesham.sadek@utsouthwestern.edu.
Hesham A
HA
Sadek
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D016166:Free Radical Scavengers / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015027:Zebrafish
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D000111:Acetylcysteine