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The endoplasmic reticulum stress and the HIF ‐1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia
Author(s) -
LópezHernández Beatriz,
Ceña Valentin,
Posadas Inmaculada
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13095
Subject(s) - unfolded protein response , endoplasmic reticulum , microbiology and biotechnology , hypoxia (environmental) , neuroprotection , apoptosis , signal transduction , biology , chop , protein phosphatase 1 , chemistry , phosphatase , phosphorylation , biochemistry , pharmacology , organic chemistry , oxygen
Background and Purpose Hypoxia inducible factor‐1 ( HIF ‐1) promotes transitory neuronal survival suggesting that additional mechanisms such as the endoplasmic reticulum ( ER ) stress might be involved in determining neuronal survival or death. Here, we examined the involvement of ER stress in hypoxia‐induced neuronal death and analysed the relationship between ER stress and the HIF ‐1 pathways. Experimental Approach Cultures of rat cortical neurons were exposed to chemical hypoxia induced by 200 μM CoCl 2 , and its effect on neuronal viability was assessed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay and counting apoptotic nuclei. Protein levels were determined by Western blot analysis. RT ‐ PCR was performed to analyse the content and the t 1/2 of HIF ‐1α mRNA . Key Results Chemical hypoxia induced neuronal apoptosis in a time‐dependent manner and activated the ER stress PRK ‐like endoplasmic reticulum kinase ( PERK )‐dependent pathway. At later stages, chemical hypoxia increased the expression of the C/EBP homologous protein ( CHOP ) and caspase 12 activity. CoCl 2 reduced HIF ‐1α mRNA t 1/2 leading to a decrease in HIF ‐1α mRNA and protein content, simultaneously activating the ER stress PERK ‐dependent pathway. Salubrinal, a selective inhibitor of phospho‐e IF 2α phosphatase, protected neurons from chemical hypoxia by reducing CHOP levels and caspase 12 activity, and increasing the t 1/2 of HIF ‐1α mRNA and the levels of HIF ‐1α protein. Knocking down HIF ‐1α blocked the neuroprotective effects of salubrinal. Conclusions and Implications Neuronal apoptosis induced by chemical hypoxia is a process regulated by HIF ‐1α stabilization early on and by ER stress activation at later stages. Our data also suggested that HIF ‐1α levels were regulated by ER stress.