Mo Shi-Jing, Hong Jun, Chen Xu, Han Fang, Ni Yin, Zheng Yang, Liu Jing-Quan, Xu Liang, Li Qian, Yang Xiang-Hong, Sun Ren-Hua, Yin Xiao-Yu
Department of Pancreatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China; Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
Neurosci Lett. 2016 Jan 1;610:54-9. doi: 10.1016/j.neulet.2015.10.051. Epub 2015 Oct 27.
Neuronal apoptosis is a contributing cause of disability and death in cerebral ischemia. Nuclear factor-κB (NF-κB) may become a potential therapeutic target for hypoxic/ischemic neuron damage because NF-κB is inactivated after hypoxia exposure. Vascular endothelial growth factor (VEGF) has been found to improve neurological function recovery in cerebral ischemic injury although the exact molecular mechanisms that underlie the neuroprotective function of VEGF remain largely unknown. Here we defined the mechanism by which VEGF antagonized neuron-like PC12 cells apoptosis induced by hypoxia mimetic agent cobalt chloride (CoCl2) is through restoration of NF-κB activity. Depletion of VEGF with small interfering RNA (siRNA) in PC12 cells conferred CoCl2-induced cytotoxicity which was mitigated by VEGF administration. Treatment of PC12 cells with VEGF attenuated the CoCl2-induced cytotoxicity in both dose- and time-dependent manner. Mechanistically, VEGF increased IκBα phosphorylation and ubiquitination, promoted P65 nuclear translocation as well as upregulated XIAP and CCND1 expression. Meanwhile, VEGF administration reversed the dysregulation of IκBα phosphorylation and ubiquitination, P65 nuclear translocation as well as XIAP and CCND1 expression induced by CoCl2. Notably, the VEGF-dependent cytoprotection was abolished by pretreatment with BAY 11-7085, a specific inhibitor of NF-κB. Our data suggest that VEGF/NF-κB signalling pathway represents an adaptive mechanism that protects neural cells against hypoxic damage.
神经元凋亡是导致脑缺血性残疾和死亡的一个原因。核因子-κB（NF-κB）可能成为缺氧/缺血性神经元损伤的潜在治疗靶点，因为缺氧暴露后NF-κB会失活。血管内皮生长因子（VEGF）已被发现可改善脑缺血损伤后的神经功能恢复，尽管VEGF神经保护功能的确切分子机制仍 largely未知。在这里，我们确定了VEGF拮抗缺氧模拟剂氯化钴（CoCl2）诱导的神经元样PC12细胞凋亡的机制是通过恢复NF-κB活性。用小干扰RNA（siRNA）耗尽PC12细胞中的VEGF会导致CoCl2诱导的细胞毒性，而VEGF给药可减轻这种毒性。用VEGF处理PC12细胞以剂量和时间依赖性方式减弱了CoCl2诱导的细胞毒性。从机制上讲，VEGF增加了IκBα的磷酸化和泛素化，促进了P65的核转位以及上调了XIAP和CCND1的表达。同时，VEGF给药逆转了CoCl2诱导的IκBα磷酸化和泛素化、P65核转位以及XIAP和CCND1表达的失调。值得注意的是，用NF-κB的特异性抑制剂BAY 11-7085预处理消除了VEGF依赖性的细胞保护作用。我们的数据表明，VEGF/NF-κB信号通路代表了一种保护神经细胞免受缺氧损伤的适应性机制。
