title: p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.
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.
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors: Chang-Lung
authors: CL
authors: Lee
authors: Everett J
authors: EJ
authors: Moding
authors: Kyle C
authors: KC
authors: Cuneo
authors: Yifan
authors: Y
authors: Li
authors: Julie M
authors: JM
authors: Sullivan
authors: Lan
authors: L
authors: Mao
authors: Iman
authors: I
authors: Washington
authors: Laura B
authors: LB
authors: Jeffords
authors: Rafaela C
authors: RC
authors: Rodrigues
authors: Yan
authors: Y
authors: Ma
authors: Shiva
authors: S
authors: Das
authors: Christopher D
authors: CD
authors: Kontos
authors: Yongbaek
authors: Y
authors: Kim
authors: Howard A
authors: HA
authors: Rockman
authors: David G
authors: DG
authors: Kirsch
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002199:Capillary Permeability / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism*; D005471:Fluoroscopy; D017353:Gene Deletion; D019426:Integrases; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology*; D009336:Necrosis; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011878:Radiotherapy / Q000009:adverse effects*; D042787:Receptor, TIE-2 / Q000235:genetics; D013599:Systole / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D042787:Receptor, TIE-2; D054462:p21-Activated Kinases; C045073:Cre recombinase; D019426:Integrases