Cold Inducible RNA Binding Protein Is Involved in Chronic Hypoxia Induced Neuron Apoptosis by Down-Regulating HIF-1α Expression and Regulated By microRNA-23a

• Published in: International journal of biological sciences Vol. 13; no. 4; pp. 518 - 531
• Main Authors: Chen, Xiaoming, Liu, Xinqin, Li, Bin, Zhang, Qian, Wang, Jiye, Zhang, Wenbin, Luo, Wenjing, Chen, Jingyuan
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2017; Ivyspring International Publisher
• Subjects: Animal models; Animals; Apoptosis; Apoptosis - genetics; Apoptosis - physiology; Blotting, Western; Cell culture; Cell Line, Tumor; Cellular stress response; Cognitive ability; Cold Temperature; Crosstalk; Environmental stress; Exposure; Flow Cytometry; High altitude; Humans; Hypoxia; Hypoxia - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunofluorescence; Male; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Neurons - cytology; Neurons - metabolism; Neuroprotection; Overexpression; Proteins; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Research Paper; Ribonucleic acid; RNA; RNA-binding protein; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Rodents; Signal Transduction; Tissue culture; microRNA; cold inducible RNA binding protein; chronic hypobaric hypoxia; hypoxia inducible factor
• ISSN: 1449-2288; 1449-2288
• DOI: 10.7150/ijbs.17800

Neuron apoptosis mediated by hypoxia inducible factor 1α (HIF-1α) in hippocampus is one of the most important factors accounting for the chronic hypobaric hypoxia induced cognitive impairment. As a neuroprotective molecule that is up-regulated in response to various environmental stress, CIRBP was reported to crosstalk with HIF-1α under cellular stress. However, its function under chronic hypobaric hypoxia remains unknown. In this study, we tried to identify the role of CIRBP in HIF-1α mediated neuron apoptosis under chronic hypobaric hypoxia and find a possible method to maintain its potential neuroprotective in long-term high altitude environmental exposure. We established a chronic hypobaric hypoxia rat model as well as a tissue culture model where SH-SY5Y cells were exposed to 1% hypoxia. Based on these models, we measured the expressions of HIF-1α and CIRBP under hypoxia exposure and examined the apoptosis of neurons by TUNEL immunofluorescence staining and western blot analysis of apoptosis related proteins. In addition, by establishing HIF-1α shRNA and pEGFP-CIRBP plasmid transfected cells, we confirmed the role of HIF-1α in chronic hypoxia induced neuron apoptosis and identified the influence of CIRBP over-expression upon HIF-1α and neuron apoptosis in the process of exposure. Furthermore, we measured the expression of the reported hypoxia related miRNAs in both models and the influence of miRNAs' over-expression/knock-down upon CIRBP in the process of HIF-1α mediated neuron apoptosis. HIF-1α expression as well as neuron apoptosis was significantly elevated by chronic hypobaric hypoxia both and . CIRBP was induced in the early stage of exposure (3d/7d); however as the exposure was prolonged (21d), CIRBP level of the hypoxia group became significantly lower than that of control. In addition, HIF-1α knockdown significantly decreased neuron apoptosis under hypoxia, suggesting HIF-1α may be pro-apoptotic in the process of exposure. CIRBP over-expression significantly suppressed HIF-1α up-regulation in hypoxia and inhibited HIF-1α mediated neuron apoptosis. Interestingly, miR-23a was also induced by hypoxia exposure and showed the same changing tendency with CIRBP (increasing in 3d/7d, decreasing in 21d). In addition, over-expressing miR-23a up-regulated CIRBP, down-regulated HIF-1α and attenuated neuron apoptosis. Cold inducible RNA binding protein is involved in chronic hypoxia induced neuron apoptosis by down-regulating HIF-1α expression, and MiR-23a may be an important tool to maintain CIRBP level and function.