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

• Published in: Brain research 2009-07, Vol.1280, p.43-51
• Main Authors: Schneider, Christina, Krischke, Gudrun, Keller, Stephan, Walkinshaw, Gail, Arend, Michael, Rascher, Wolfgang, Gassmann, Max, Trollmann, Regina
• Format: Article
• Language: English
• Subjects: Adrenomedullin; Adrenomedullin - metabolism; Animals; Animals, Newborn; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biological and medical sciences; Brain - drug effects; Brain - growth & development; Brain - metabolism; Chemokine receptor CXCR-4; Developing mouse brain; Development. Senescence. Regeneration. Transplantation; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Erythropoietin; Erythropoietin - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression - drug effects; Hexokinase - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible transcription factor; Kidney - drug effects; Kidney - growth & development; Kidney - metabolism; Mice; Mice, Inbred C57BL; Neurology; Nitric Oxide Synthase Type II - metabolism; Procollagen-Proline Dioxygenase - antagonists & inhibitors; Procollagen-Proline Dioxygenase - metabolism; Receptors, CXCR4 - metabolism; RNA, Messenger - metabolism; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2009.05.023

Abstract 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.