title: VEGF-mediated NF-κB activation protects PC12 cells from damage induced by hypoxia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shi-Jing
authors.initials: SJ
authors.lastname: Mo
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China.
authors.forename: Xiang-Hong
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, China. Electronic address: jqin168@hotmail.com.
authors.forename: Ren-Hua
authors.initials: RH
authors.lastname: Sun
authors.affiliation: Department of Pancreatobiliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China. Electronic address: dr_yinxy@163.com.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Yin
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D003035:Cobalt / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; C018021:cobaltous chloride
keywords: Apoptosis; Hypoxia; NF-κB; VEGF