Yang Yong, Xi Zhiyu, Xue Yuan, Ren Jie, Sun Yuhao, Wang Baofeng, Zhong Zhihong, Yang Guo-Yuan, Sun Qingfang, Bian Liuguan
Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
Zhenjiang Center for Disease Control and Prevention, Zhenjiang 212000, China.
Exp Cell Res. 2017 Dec 15;361(2):217-224. doi: 10.1016/j.yexcr.2017.10.020. Epub 2017 Oct 24.
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.
氧化应激介导的继发性损伤会导致脑出血（ICH）后的神经功能恶化。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发挥关键作用。血红蛋白（Hb）是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Hb降解的产物，由于诱导活性氧（ROS）而具有高毒性。我们推测Hb激活的星形胶质细胞对血红素诱导的毒性具有抗性。为了验证我们的推测，将经Hb预处理的星形胶质细胞暴露于血红素中，评估细胞内ROS积累和细胞凋亡情况。观察血红素加氧酶1（HO-1）和核转录因子-红系2相关因子（Nrf2）的表达以探索潜在机制。结果表明，Hb诱导星形胶质细胞中Nrf2的上调和核转位，导致HO-1上调，这有助于减少ROS积累和凋亡率。通过小干扰RNA（siRNA）敲低Nrf2表达可抑制Hb诱导的HO-1表达上调，并增加经Hb预处理的星形胶质细胞对血红素诱导毒性的敏感性。综上所述，Hb激活的星形胶质细胞通过Nrf2/HO-1途径获得了对血红素诱导毒性的抗性。这种现象可被视为ICH病理过程中的适应性自我防御。Hb预先警告星形胶质细胞并增强了它们处理即将到来的血红素“洪流”的能力。Nrf2/HO-1可能被用作ICH后神经保护的靶点。
