Ataxia Telangiectasia Mutated (ATM)-mediated DNA Damage Response in Oxidative Stress-induced Vascular Endothelial Cell Senescence*
Ataxia Telangiectasia Mutated (ATM)-mediated DNA Damage Response in Oxidative Stress-induced Vascular Endothelial Cell Senescence*
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DOI：
10.1074/jbc.m110.125138
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
Hong Zhan;Toru Suzuki;K. Aizawa;K. Miyagawa;R. Nagai
中科院分区：
文献类型：
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作者：
Hong Zhan;Toru Suzuki;K. Aizawa;K. Miyagawa;R. Nagai
氧化应激调节血管内皮细胞功能障碍和衰老。涉及共济失调毛细血管扩张突变（ATM）的DNA损伤反应及其主要信号通路在介导氧化应激的作用中起着重要作用;然而，ATM信号通路在血管发病机制中的作用在很大程度上仍不清楚。在这里，我们确定ATM调节氧化应激诱导的内皮细胞功能障碍和过早衰老。氧化应激通过Akt/p53/p21介导的ATM活化/磷酸化途径诱导内皮细胞衰老。在ATM被RNA干扰敲低或被特定抑制化合物抑制的细胞中，这些作用被废除。此外，使用ATM敲除小鼠证实了该调节途径的体内意义，其中与野生型小鼠中观察到的病理变化相比，在内皮功能障碍和衰老的糖尿病小鼠模型中主动脉中衰老内皮细胞的诱导减弱。总的来说，我们的研究结果表明，ATM通过ATM/Akt/p53/p21依赖的信号通路介导的氧化应激诱导的内皮功能障碍和过早衰老的指导作用。
Oxidative stress regulates dysfunction and senescence of vascular endothelial cells. The DNA damage response and its main signaling pathway involving ataxia telangiectasia mutated (ATM) have been implicated in playing a central role in mediating the actions of oxidative stress; however, the role of the ATM signaling pathway in vascular pathogenesis has largely remained unclear. Here, we identify ATM to regulate oxidative stress-induced endothelial cell dysfunction and premature senescence. Oxidative stress induced senescence in endothelial cells through activation/phosphorylation of ATM by way of an Akt/p53/p21-mediated pathway. These actions were abrogated in cells in which ATM was knocked down by RNA interference or inhibited by specific inhibitory compounds. Furthermore, the in vivo significance of this regulatory pathway was confirmed using ATM knock-out mice in which induction of senescent endothelial cells in the aorta in a diabetic mouse model of endothelial dysfunction and senescence was attenuated in contrast to pathological changes seen in wild-type mice. Collectively, our results show that ATM through an ATM/Akt/p53/p21-dependent signaling pathway mediates an instructive role in oxidative stress-induced endothelial dysfunction and premature senescence.