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Vitamin C is dispensable for oxygen sensing in vivo


Nytko, K J; Nobuyo, M; Schlaefli, P; Spielmann, P; Wenger, R H; Stiehl, D P (2011). Vitamin C is dispensable for oxygen sensing in vivo. Blood, 117(20):5485-5493.

Abstract

Prolyl-4-hydroxylation is necessary for proper structural assembly of collagens and oxygen-dependent protein stability of hypoxia-inducible transcription factors (HIFs). In vitro function of HIF prolyl-4-hydroxylase domain (PHD) enzymes requires oxygen and 2-oxoglutarate as co-substrates with iron (II) and vitamin C serving as co-factors. While vitamin C deficiency is known to cause the collagen-disassembly disease scurvy, it is unclear whether cellular oxygen sensing is similarly affected. Here we report that vitamin C deprived Gulo(-/-) knock-out mice show normal HIF-dependent gene expression. The systemic response of Gulo(-/-) animals to inspiratory hypoxia, as measured by plasma erythropoietin levels, was similar to animals supplemented with vitamin C. Hypoxic HIF induction was also essentially normal under serum- and vitamin C-free cell culture conditions, suggesting that vitamin C is not required for oxygen sensing in vivo. Glutathione was found to fully substitute for vitamin C requirement of all three PHD isoforms in vitro. Consistently, glutathione also reduced HIF-1α protein levels, transactivation activity and endogenous target gene expression in cells exposed to CoCl(2). A C201S mutation in PHD2 increased basal hydroxylation rates and conferred resistance to oxidative damage in vitro, suggesting that this surface accessible PHD2 cysteine residue is a target of antioxidative protection by vitamin C and glutathione.

Prolyl-4-hydroxylation is necessary for proper structural assembly of collagens and oxygen-dependent protein stability of hypoxia-inducible transcription factors (HIFs). In vitro function of HIF prolyl-4-hydroxylase domain (PHD) enzymes requires oxygen and 2-oxoglutarate as co-substrates with iron (II) and vitamin C serving as co-factors. While vitamin C deficiency is known to cause the collagen-disassembly disease scurvy, it is unclear whether cellular oxygen sensing is similarly affected. Here we report that vitamin C deprived Gulo(-/-) knock-out mice show normal HIF-dependent gene expression. The systemic response of Gulo(-/-) animals to inspiratory hypoxia, as measured by plasma erythropoietin levels, was similar to animals supplemented with vitamin C. Hypoxic HIF induction was also essentially normal under serum- and vitamin C-free cell culture conditions, suggesting that vitamin C is not required for oxygen sensing in vivo. Glutathione was found to fully substitute for vitamin C requirement of all three PHD isoforms in vitro. Consistently, glutathione also reduced HIF-1α protein levels, transactivation activity and endogenous target gene expression in cells exposed to CoCl(2). A C201S mutation in PHD2 increased basal hydroxylation rates and conferred resistance to oxidative damage in vitro, suggesting that this surface accessible PHD2 cysteine residue is a target of antioxidative protection by vitamin C and glutathione.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2011
Deposited On:11 Mar 2011 08:47
Last Modified:05 Apr 2016 14:52
Publisher:American Society of Hematology
ISSN:0006-4971
Funders:NIH , SNF, Forschungskredit University Zurich
Additional Information:Copyright by the American Society of Hematology
Publisher DOI:https://doi.org/10.1182/blood-2010-09-307637
PubMed ID:21346252
Permanent URL: https://doi.org/10.5167/uzh-47509

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