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Fluoxetine induces vascular endothelial growth factor/Netrin over‐expression via the mediation of hypoxia‐inducible factor 1‐alpha in SH ‐ SY 5Y cells
Author(s) -
Wang Jiayi,
Zhou Xiaoyu,
Lu Haiyan,
Song Mingrui,
Zhao Jinglong,
Wang Qiaoshu
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13521
Subject(s) - vascular endothelial growth factor , chromatin immunoprecipitation , hypoxia (environmental) , vascular endothelial growth factor a , hif1a , transcription factor , netrin , biology , angiogenesis , promoter , cancer research , microbiology and biotechnology , endocrinology , chemistry , gene expression , gene , biochemistry , axon guidance , organic chemistry , oxygen , axon , vegf receptors
Fluoxetine has become one of the most promising drugs for improving clinical outcome in patients with cerebral infarction. Although the clinical efficacy of fluoxetine has been preliminarily demonstrated, its mechanism remains unclear. Hypoxia‐inducible factor 1‐alpha ( HIF ‐1α) is upstream to Netrin and vascular endothelial growth factor ( VEGF ), and under hypoxia conditions it may induce expression of Netrin‐1 and VEGF in vascular endothelial cells. We sought to explore whether it can regulate their expression in hypoxia and mediate the effect of fluoxetine in hypoxia. In this study, the effect of hypoxia on the expression of VEGF and Netrin was observed in vitro by real‐time PCR and western blotting in SH ‐ SY 5Y cells; the binding sites of HIF ‐1α in VEGF and Netrin gene promoters were identified by luciferase reporter; the effect of fluoxetine on binding of HIF ‐1α with Netrin and VEGF promoters in hypoxia was observed by Chromatin Immunoprecipitation (Ch IP ) Assay. We prove that HIF ‐1α regulates transcription of both VEGF and Netrin, and that in hypoxia fluoxetine up‐regulates VEGF and Netrin expression via mediation of HIF ‐1α that binds to hypoxia‐response element sites of VEGF and Netrin promoters. Our study indicates that HIF ‐1α may play an important role in the treatment of cerebral infarction through mediating the recovery of neurological function induced by fluoxetine, which provides theoretical basis for the development of gene therapeutic drugs targeting HIF ‐1α.We show that hypoxia‐inducible factor 1‐alpha (HIF‐1α) regulates transcription of both vascular endothelial growth factor (VEGF) and Netrin. Furthermore, we also show that in hypoxia fluoxetine up‐regulates VEGF and Netrin expression via mediation of HIF‐1α that binds to hypoxia‐response element (HRE) sites of VEGF and Netrin promoters. Our study indicates that HIF‐1α may play an important role in the treatment of cerebral infarction through mediating the recovery of neurological function induced by fluoxetine. These findings provide a theoretical basis for development of gene therapeutic drugs targeting HIF‐1α.