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

Abstract

p53 functions in the heart to promote myocardial injury after multiple types of stress. However, how p53 regulates radiation-induced myocardial injury, which develops after radiation therapy, is not well understood. Here, we utilize the Cre-loxP system to demonstrate 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 due to 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 using primary cardiac endothelial cells irradiated in vitro indicated that p53 signaling caused mitotic arrest and protected cardiac endothelial cells against radiation-induced 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 wholeheart irradiation. Together, our results demonstrate that the p53/p21 axis functions to prevent radiation-induced myocardial injury in mice.

Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium

“…Recently, we reported that cardiac endothelial cells lacking p53 or p21 are sensitized to radiation (11). Furthermore, mice lacking p21 or mice lacking p53 specifically in endothelial cells were sensitized to radiation-induced myocardial necrosis (11). Here, we found that deletion of p53 in endothelial cells not only permitted Atm deletion to sensitize endothelial cells to radiation in vitro, but also allowed Atm deletion to accelerate radiation-induced myocardial necrosis in vivo.…”

“…Our present results suggested that the abrogation of cell cycle checkpoints allows quiescent cells to be sensitized to radiation as a consequence of Atm deletion. Recently, we reported that cardiac endothelial cells lacking p53 or p21 are sensitized to radiation (11). Furthermore, mice lacking p21 or mice lacking p53 specifically in endothelial cells were sensitized to radiation-induced myocardial necrosis (11).…”

“…Although we previously showed that endothelial cell damage is sufficient to cause radiation-induced myocardial necrosis (11), it is likely that other cell types can also contribute to radiation-induced heart disease. In addition, the contribution of each cell type may depend on the dose and fractionation of radiation therapy.…”

“…Although these inhibitors have been shown to radiosensitize tumor cell lines and xenografts (9), concern over radiosensitization of normal tissues may limit their clinical application. For example, we previously demonstrated that cell type-specific deletion of the ATM phosphorylation target p53 sensitizes mice to radiation-induced gastrointestinal injury (10) and myocardial necrosis (11). Although Atm-knockout mice have been used to study acute radiation injury, these mice are tumor prone (12,13).…”

Attenuation of Diabetes-Induced Cardiac Inflammation and Pathological Remodeling by Low-Dose Radiation

“…Whole-heart 12 Gy irradiation led to impaired systolic function, cardiac hypertrophy, vascular remodeling, myocardial hypoxia, necrosis and ischemia. Mice lacking p21, a transcriptional target of p53, also developed myocardial degeneration, necrosis, systolic dysfunction and cardiac hypertrophy after whole-heart 12 Gy irradiation (66).…”