Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain

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• 作者：Christina Schneider ; Gudrun Krischke ; Stephan Keller ; Gail Walkinshaw ; Michael Arend ; Wolfgang Rascher ; Max Gassmann ; Regina Trollmann
• 关键词：Hypoxia-inducible transcription factor ; Vascular endothelial growth factor ; Chemokine receptor CXCR-4 ; Erythropoietin ; Adrenomedullin ; Developing mouse brain
• 刊名：Brain Research
• 出版年：2009
• 出版时间：14 July 2009
• 年：2009
• 卷：1280
• 期：Complete
• 页码：43-51
• 全文大小：633 K

文摘

Hypoxia-inducible transcription factors (HIFs) are crucially involved in brain development and cellular adaptation to hypoxia and ischemia. Degradation of HIF is regulated under normoxia by oxygen-dependent hydroxylation of specific prolyl residues on the labile α-subunit by HIF prolyl hydroxylases (PHD). Prolyl-4-hydroxylase inhibitors (PHI) have shown protective effects in vitro and in vivo in adult kidney and brain. The aim of the present study was to investigate in vivo short-term effects of a novel low molecular weight PHI, FG-4497, on HIF-regulated cytotrophic and vasoactive factors in developing mouse brain. Neonatal (P7, n  = 26) C57/BL6 mice were treated with PHI FG-4497 (30–100 mg/kg, i.p., duration 6 h). Gene expression was analyzed by TaqMan RT-PCR in kidney and developing brain in comparison to controls (NaCl 0.9 % and non-treated animals). HIF-1α protein was quantified by Western blot analysis. Dose–response studies revealed prominent effects of FG-4497 at a dose of 100 mg/kg as assessed by significant up-regulation of mRNA in both kidney and brain of the following HIF-dependent genes: vascular endothelial growth factor, adrenomedullin and erythropoietin. Organ-specific transcriptional regulation was evident from analysis of hexokinase 2, inducible NO synthase and PHD3 mRNA concentrations. In the brain, HIF-1α and HIF-2α protein markedly accumulated in response to FG-4497. Besides vasoactive factors, PHI significantly increased cerebral chemokine receptor CXCR-4 mRNA levels. In conclusion, the novel PHI FG-4497 activates HIFs at an early stage of brain maturation and modulates neurotrophic processes known to be crucially involved in brain development and hypoxia-induced brain pathology.