Hemoglobin pretreatment endows rat cortical astrocytes resistance to hemin-induced toxicity via Nrf2/HO-1 pathway
Hemoglobin pretreatment endows rat cortical astrocytes resistance to hemin-induced toxicity via Nrf2/HO-1 pathway
复制标题
血红蛋白预处理通过 Nrf2/HO-1 途径赋予大鼠皮质星形胶质细胞对血红素诱导的毒性的抵抗力
DOI：
10.1016/j.yexcr.2017.10.020
复制
发表时间：
2017
影响因子：
3.7
通讯作者：
Bian Liuguan
中科院分区：
文献类型：
--
作者：
Yang Yong;Xi Zhiyu;Xue Yuan;Ren Jie;Sun Yuhao;Wang Baofeng;Zhong Zhihong;Yang Guo-yuan;Sun Qingfang;Bian Liuguan
氧化应激介导的继发性损伤有助于脑出血（ICH）后神经功能的恶化。星形胶质细胞是中枢神经系统（CNS）中最主要的细胞，通过提供氧化应激防御在维持氧化还原稳态中起关键作用。血红蛋白（Hb）是由溶血释放的主要成分，是星形胶质细胞的有效激活剂。血红素是血红蛋白降解的产物，由于诱导活性氧（ROS）而具有高度毒性。我们推测血红蛋白激活的星形胶质细胞对氯化血红素诱导的毒性有抵抗力。为了验证我们的推测，血红蛋白预处理的星形胶质细胞暴露于氯化血红素，细胞内ROS积累和细胞凋亡进行了评估。观察血红素加氧酶1（HO-1）和核转录因子-红细胞相关因子2（Nrf 2）的表达，探讨其可能的机制。结果表明，Hb可诱导星形胶质细胞Nrf 2表达上调和核转位，导致HO-1表达上调，从而降低ROS的积累和凋亡率。通过siRNA敲低Nrf 2表达抑制Hb诱导的HO-1表达上调，并增加Hb预处理的星形胶质细胞对氯化血红素诱导的毒性的敏感性。总之，血红蛋白激活的星形胶质细胞获得通过Nrf 2/HO-1途径对氯化血红素诱导的毒性的抗性。这一现象可被认为是脑出血病理过程中的一种适应性自我防御机制。血红蛋白对星形胶质细胞具有预警作用，增强了星形胶质细胞应对即将到来的氯化血红素“洪水”的能力。Nrf 2/HO-1可作为脑出血后神经保护的靶点。
Oxidative stress mediated secondary injury contributes to neurological deterioration after intracerebral hemorrhage (ICH). Astrocytes, the most dominant cells in the central nervous system (CNS), play key roles in maintaining redox homeostasis by providing oxidative stress defense. Hemoglobin (Hb), the primary component released by hemolysis, is an effective activator of astrocytes. Hemin, the product of Hb degradation, is highly toxic due to the induction of reactive oxygen species (ROS). We speculate that Hb-activated astrocytes are resistant to hemin-induced toxicity. To verify our speculation, Hb-pretreated astrocytes were exposed to hemin, intracellular ROS accumulation and cell apoptosis were evaluated. Heme oxygenase 1 (HO-1) and nuclear transcription factor-erythroid 2 related factor (Nrf2) expression were observed to explore the potential mechanism. The results demonstrated that Hb induced upregulation and nuclear translocation of Nrf2 in astrocytes, resulted in HO-1 upregulation, which contributed to reduced ROS accumulation and apoptosis rate. Knocking down Nrf2 expression by siRNA suppressed Hb-induced upregulation of HO-1 expression and increased the susceptibility of Hb-pretreated astrocytes to hemin-induced toxicity. Taken together, Hb-activated astrocytes acquired resistance to hemin-induced toxicity via Nrf2/HO-1 pathway. This phenomenon can be considered as the adaptive self-defense in the pathological process of ICH. Hb pre-warned astrocytes and enhanced their capability of handling the coming hemin “flood”. Nrf2/HO-1 may be employed as a target for neuroprotection after ICH.