Low temperature protects mammalian cells from apoptosis initiated by various stimuli in vitro
Low temperature protects mammalian cells from apoptosis initiated by various stimuli in vitro
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DOI：
10.1016/j.yexcr.2005.06.002
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发表时间：
2005-10-01
影响因子：
3.7
通讯作者：
Fujita, J
中科院分区：
文献类型：
--
作者：
Sakurai, T;Itoh, K;Fujita, J
亚低温对脑损伤和心脏骤停患者具有保护作用。为了阐明这些效应背后的分子机制，我们在体外检测了低温(32摄氏度)对暴露于各种压力下的细胞的影响。我们发现，32摄氏度抑制了阿霉素、依托泊苷、thapsigargin、NaC l、H_2O_2和抗Fas抗体等细胞毒刺激诱导的细胞凋亡。在阿霉素处理的BALB/3T3细胞中，温度从37℃下降到32℃时，BALB/3T3细胞中的Bclxl蛋白水平升高，Puma基因表达水平降低，Bax基因的线粒体易位减少，从而抑制caspase-9介导的细胞凋亡。此外，随着MDM2基因表达的上调，P53蛋白水平和稳定性降低，核输出增加。在P53(-/-)/MDM2(-/-)小鼠胚胎成纤维细胞中未观察到低温作用，提示该作用是通过抑制P53途径实现的。相反，尽管thapsigargin诱导的细胞凋亡被低温抑制，但对P53蛋白水平没有影响。此外，暴露于thapsigargin的p53(-/-)/MDM2(-/-)细胞在32℃培养时的存活率高于37℃培养的细胞。结论：亚低温通过P53依赖和P53非依赖的机制保护细胞免受各种应激。(C)2005 Elsevier Inc.保留所有权利。
Mild hypothermia shows protective effects on patients with brain damage and cardiac arrest. To elucidate the molecular mechanisms underlying these effects, we examined the effects of low temperature (32 degrees C) on cells exposed to a variety of stress in vitro. We found that 32 degrees C suppressed induction of apoptosis by cytotoxic stimuli such as adriamycin, etoposide, thapsigargin, NaCl, H2O2, and anti-Fas antibody. In adriamycin-treated BALB/3T3 cells, the down-shift in temperature from 37 degrees C to 32 degrees C increased the Bcl-xL protein level and decreased the mRNA level of Puma and mitochondrial translocation of Bax, suppressing caspase-9-mediated apoptosis. Furthermore, the protein level and stability of p53 were decreased, and its nuclear export was increased concomitant with Mdm2 mRNA upregulation. The low temperature effect was not observed in p53(-/-)/Mdm2(-/-) mouse embryonic fibroblasts, suggesting that the effect is mediated by suppression of the p53 pathway. In contrast, while thapsigargin-induced apoptosis was suppressed by the low temperature, no effect on the p53 protein level was observed. Furthermore, the survival rate of p53(-/-)/Mdm2(-/-) cells exposed to thapsigargin was increased when cultured at 32 degrees C compared with 37 degrees C. In conclusion, mild hypothermia protects cells from a variety of stress by p53-dependent and p53-independent mechanisms. (c) 2005 Elsevier Inc. All rights reserved.