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首页> 外文期刊>Journal of neuroinflammation >Hypothermia enhances induction of protective protein metallothionein under ischemia
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Hypothermia enhances induction of protective protein metallothionein under ischemia

机译：低温可增强缺血下保护性蛋白金属硫蛋白的诱导

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Background Hypothermic protection against ischemic stroke has been reported by many studies. Hypothermia is supposed to mitigate the effects of deleterious genes and proteins and promote the activity of protective genes and proteins in the ischemic brain. Metallothionein (MT)-1/2 is thought to be a crucial factor for metal homeostasis, immune function, and apoptosis. This protein was found to exert protective effects in models of brain injury as well. In the present study, we investigated the effect of hypothermia on MT expression and the underlying mechanisms. Methods Cultured bEnd.3 brain endothelial cells were exposed to oxygen glucose deprivation and reperfusion (OGD+R). Reverse transcription PCR and western blot analyses were performed to measure the expression of MT, transcription factors, and methylation regulating factors. Transcription factor binding assays were also performed. Methylation profiles of the promoter area were obtained with pyrosequencing. Results Hypothermia protected bEnd.3 cells from OGD+R. When the cells were exposed to OGD+R, MT expression was induced. Hypothermia augmented MT levels. While OGD+R-induced MT expression was mainly associated with metal regulatory transcription factor 1 (MTF-1), MT expression promoted by hypothermia was primarily mediated by the signal transducer and activator of transcription 3 (STAT3). Significantly increased STAT3 phosphorylation at Ser727 was observed with hypothermia, and JSI-124, a STAT-3 inhibitor, suppressed MT expression. The DNA demethylating drug 5-aza-2′-deoxycytidine (5-Aza) enhanced MT expression. Some of the CpG sites in the promoter MT=> it should be “the CpG sites in the MT promoter” showed different methylation profiles and some methylation regulating factors had different expressional profiles in the presence of OGD+R and hypothermia. Conclusions We demonstrated that hypothermia is a potent inducer of MT gene transcription in brain endothelial cells, and enhanced MT expression might contribute to protection against ischemia. MT gene expression is induced by hypothermia mainly through the STAT3 pathway. DNA methylation may contribute to MT gene regulation under ischemic or hypothermic conditions.
机译：背景许多研究报道了针对缺血性中风的低温保护。体温过低被认为可以减轻有害基因和蛋白质的影响，并促进缺血性脑中保护性基因和蛋白质的活性。金属硫蛋白（MT）-1/2被认为是金属稳态，免疫功能和细胞凋亡的关键因素。还发现该蛋白在脑损伤模型中也发挥保护作用。在本研究中，我们调查了低温对MT表达的影响及其潜在机制。方法将培养的bEnd.3脑内皮细胞暴露于氧葡萄糖剥夺和再灌注（OGD + R）。进行逆转录PCR和蛋白质印迹分析以测量MT，转录因子和甲基化调节因子的表达。还进行了转录因子结合测定。通过焦磷酸测序获得启动子区域的甲基化分布图。结果亚低温保护bEnd.3细胞免受OGD + R的侵害。当细胞暴露于OGD + R时，诱导了MT表达。体温过低会增加MT水平。虽然OGD + R诱导的MT表达主要与金属调节转录因子1（MTF-1）相关，但是低温引起的MT表达主要由信号转导和转录激活因子3（STAT3）介导。体温过低，观察到Ser727处STAT3磷酸化显着增加，而STAT-3抑制剂JSI-124抑制MT表达。 DNA脱甲基药物5-aza-2'-脱氧胞苷（5-Aza）增强了MT表达。启动子MT中的某些CpG位点应为“ MT启动子中的CpG位点”，显示出不同的甲基化谱，而某些甲基化调节因子在OGD + R和体温过低的情况下具有不同的表达谱。结论我们证明了体温过低是脑内皮细胞MT基因转录的有效诱导剂，增强的MT表达可能有助于预防缺血。低温主要通过STAT3途径诱导MT基因表达。 DNA甲基化可能有助于缺血或低温条件下的MT基因调控。

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