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Sci. Signal., 24 July 2012
Vol. 5, Issue 234, p. ra52
[DOI: 10.1126/scisignal.2002918]

RESEARCH ARTICLES

p53 Functions in Endothelial Cells to Prevent Radiation-Induced Myocardial Injury in Mice

Chang-Lung Lee1, Everett J. Moding1, Kyle C. Cuneo2, Yifan Li2, Julie M. Sullivan2, Lan Mao3, Iman Washington2, Laura B. Jeffords2, Rafaela C. Rodrigues2, Yan Ma2, Shiva Das2, Christopher D. Kontos1,3, Yongbaek Kim4, Howard A. Rockman3, and David G. Kirsch1,2*

1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
2 Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
4 Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, South Korea.

Abstract: Radiation therapy, which is used for the treatment of some cancers, can cause delayed heart damage. In the heart, p53 influences myocardial injury that occurs after multiple types of stress. Here, we demonstrated that p53 functioned in endothelial cells to protect mice from myocardial injury after whole-heart irradiation. Mice with an endothelial cell–specific deletion of p53 succumbed to heart failure after whole-heart irradiation as a result of myocardial necrosis, systolic dysfunction, and cardiac hypertrophy. Moreover, the onset of cardiac dysfunction was preceded by alterations in myocardial vascular permeability and density, which resulted in cardiac ischemia and myocardial hypoxia. Mechanistic studies with primary cardiac endothelial cells irradiated in vitro indicated that p53 signaling caused mitotic arrest and protected cardiac endothelial cells from cell death resulting from abnormal mitosis or mitotic catastrophe. Furthermore, mice lacking the cyclin-dependent kinase inhibitor p21, which is a transcriptional target of p53, were also sensitized to myocardial injury after whole-heart irradiation. Together, our results demonstrate that the p53-p21 axis functions to prevent radiation-induced myocardial injury in mice.

* To whom correspondence should be addressed. E-mail: david.kirsch{at}duke.edu

Citation: C.-L. Lee, E. J. Moding, K. C. Cuneo, Y. Li, J. M. Sullivan, L. Mao, I. Washington, L. B. Jeffords, R. C. Rodrigues, Y. Ma, S. Das, C. D. Kontos, Y. Kim, H. A. Rockman, D. G. Kirsch, p53 Functions in Endothelial Cells to Prevent Radiation-Induced Myocardial Injury in Mice. Sci. Signal. 5, ra52 (2012).

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