p53 is required for chloroquine-induced atheroprotection but not insulin sensitization
p53 is required for chloroquine-induced atheroprotection but not insulin sensitization
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DOI：
10.1194/jlr.m003681
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发表时间：
2010-07-01
影响因子：
6.5
通讯作者：
Semenkovich, Clay F.
中科院分区：
文献类型：
--
作者：
Razani, Babak;Feng, Chu;Semenkovich, Clay F.
一个完整的基因毒性应激反应似乎是动脉粥样硬化保护和胰岛素增敏。ATM在共济失调毛细血管扩张中发生突变，对基因毒性应激反应至关重要，其缺乏与人类和小鼠的动脉粥样硬化加速和胰岛素抵抗有关。抗疟药物氯喹激活ATM信号并改善小鼠的代谢表型。p53是ATM信号的主要效应因子，但目前尚不清楚p53是否需要氯喹的有益作用。我们检验了氯喹的心脏代谢作用是p53依赖的假设。apoe缺失的小鼠，不论有无p53，在西式饮食的背景下，用低剂量氯喹或生理盐水治疗。8周后，对血脂或体重没有p53依赖性或氯喹特异性的影响。氯喹减轻了p53野生型小鼠的斑块负担，但没有减少p53缺失小鼠的病变程度。然而，与p53基因型无关，氯喹改善了葡萄糖耐量，增强了胰岛素敏感性，并增加了肝脏Akt信号。这些结果表明，氯喹诱导的动脉粥样硬化保护是p53依赖的，但该药物的胰岛素增敏作用不是p53依赖的。基因毒性应激反应的离散组成部分可能针对治疗脂质驱动的疾病，如糖尿病和动脉粥样硬化。——razani， B.， C. Feng， C. F. Semenkovich。P53是氯喹诱导的动脉粥样硬化保护所必需的，但不是胰岛素增敏所必需的。[j] .油脂杂志。2010。51: 1738 - 1746。
An intact genotoxic stress response appears to be atheroprotective and insulin sensitizing. ATM, mutated in ataxia telangiectasia, is critical for the genotoxic stress response, and its deficiency is associated with accelerated atherosclerosis and insulin resistance in humans and mice. The antimalarial drug chloroquine activates ATM signaling and improves metabolic phenotypes in mice. p53 is a major effector of ATM signaling, but it is unknown if p53 is required for the beneficial effects of chloroquine. We tested the hypothesis that the cardiometabolic effects of chloroquine are p53-dependent. ApoE-null mice with or without p53 were treated with low-dose chloroquine or saline in the setting of a Western diet. After 8 weeks, there was no p53-dependent or chloroquine-specific effect on serum lipids or body weight. Chloroquine reduced plaque burden in mice wild-type for p53, but it did not decrease lesion extent in p53-null mice. However, chloroquine improved glucose tolerance, enhanced insulin sensitivity, and increased hepatic Akt signaling regardless of the p53 genotype. These results indicate that atheroprotection induced by chloroquine is p53-dependent but the insulin-sensitizing effects of this agent are not. Discrete components of the genotoxic stress response might be targeted to treat lipid- driven disorders, such as diabetes and atherosclerosis.-Razani, B., C. Feng, and C. F. Semenkovich. p53 is required for chloroquine-induced atheroprotection but not insulin sensitization. J. Lipid Res. 2010. 51: 1738-1746.