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        Impaired hypoxic response in senescent mouse brain

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        905883.pdf (PDF, 528Kb)
        Author
        Rabie, Tamer
        Kunze, Reiner
        Marti, Hugo H.
        Attention
        2299/6761
        Abstract
        Tissue hypoxia leads to activation of endogenous adaptive responses that involve a family of prolyl hydroxylase domain proteins (PHD1-3) with oxygen sensing properties, hypoxia inducible transcription factors (HIFs), and cytoprotective HIF target genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). The hypoxic induction of these genes is regulated by oxygen-dependent hydroxylation of HIF alpha subunits by PHDs, which signals their proteasomal degradation. In this study, mice of different age were exposed to hypoxia or subjected to cerebral ischemia after hypoxic pre-conditioning. We found an impaired hypoxic response in the brain, characterized by elevated levels and impaired downregulation of PHD1. Furthermore, an attenuated hypoxic activation of VEGF and EPO, as well as of other HIF-target genes such glucose transporter-1 and carbonic anhydrase 9 was found in senescent brain. Finally, we observed a loss of the protective effect of hypoxic pre-conditioning on subsequent cerebral ischemia with increasing age. Thus, the impaired hypoxic adaptation, resulting in compromised hypoxic activation of neuroprotective factors, could contribute to neurodegenerative processes with increasing age, and might have implications for treating age-related disorders.
        Publication date
        2011-10
        Published in
        International Journal of Developmental Neuroscience
        Published version
        https://doi.org/10.1016/j.ijdevneu.2011.06.003
        Other links
        http://hdl.handle.net/2299/6761
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