The endoplasmic reticulum stress and the HIF-1 signalling pathways are involved in the neuronal damage caused by chemical hypoxia.

Autor:	López ‐ Hernández, Beatriz, Ceña, Valentin, Posadas, Inmaculada
Předmět:	ENDOPLASMIC reticulum CELLULAR signal transduction NEURONS HYPOXIA-inducible factor 1 LABORATORY rats APOPTOSIS WOUNDS & injuries PHYSIOLOGY
Zdroj:	British Journal of Pharmacology; Jun2015, Vol. 172 Issue 11, p2838-2851, 14p
Abstrakt:	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 CoCl2, 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 t1/2 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. CoCl2 reduced HIF-1α mRNA t1/2 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 IF2α phosphatase, protected neurons from chemical hypoxia by reducing CHOP levels and caspase 12 activity, and increasing the t1/2 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. [ABSTRACT FROM AUTHOR]
Databáze:	Complementary Index
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