p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.
p53 functions in endothelial cells to prevent radiation-induced myocardial injury in mice.
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DOI：
10.1126/scisignal.2002918
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发表时间：
2012-07-24
影响因子：
7.3
通讯作者：
Kirsch DG
中科院分区：
文献类型：
--
作者：
Lee CL;Moding EJ;Cuneo KC;Li Y;Sullivan JM;Mao L;Washington I;Jeffords LB;Rodrigues RC;Ma Y;Das S;Kontos CD;Kim Y;Rockman HA;Kirsch DG
多种应激后，P53在心脏中起促进心肌损伤的作用。然而，p53如何调节放射治疗后发生的放射性心肌损伤尚不清楚。在这里，我们利用Cre-loxP系统证明p53在内皮细胞中起保护小鼠全心照射后心肌损伤的作用。内皮细胞特异性缺失p53的小鼠在全心照射后因心肌坏死、收缩功能障碍和心脏肥厚而发生心力衰竭。心功能障碍发生前，心肌血管通透性和密度发生改变，导致心肌缺血和心肌缺氧。体外辐照原代心脏内皮细胞的机制研究表明，p53信号导致有丝分裂停止，并保护心脏内皮细胞免受辐射诱导的有丝分裂灾难。此外，缺乏细胞周期蛋白依赖性激酶抑制剂p21 （p53的转录靶点）的小鼠在全心照射后也对心肌损伤敏感。总之，我们的研究结果表明，p53/p21轴可以预防小鼠辐射引起的心肌损伤。
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.
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影响因子：
11.2
作者：
Kumar, Pawan;Coltas, Ila K.;Polverini, Peter J.
通讯作者：
Polverini, Peter J.
影响因子：
51.1
作者：
Darby, SC;McGale, P;Peto, R
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影响因子：
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Sigmund, Curt D.
影响因子：
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作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B