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Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors - PubMed

  • ️Mon Jan 01 2018

Review

Reactive Oxygen Species Formation in the Brain at Different Oxygen Levels: The Role of Hypoxia Inducible Factors

Ruoli Chen et al. Front Cell Dev Biol. 2018.

Abstract

Hypoxia inducible factor (HIF) is the master oxygen sensor within cells and is central to the regulation of cell responses to varying oxygen levels. HIF activation during hypoxia ensures optimum ATP production and cell integrity, and is associated both directly and indirectly with reactive oxygen species (ROS) formation. HIF activation can either reduce ROS formation by suppressing the function of mitochondrial tricarboxylic acid cycle (TCA cycle), or increase ROS formation via NADPH oxidase (NOX), a target gene of HIF pathway. ROS is an unavoidable consequence of aerobic metabolism. In normal conditions (i.e., physioxia), ROS is produced at minimal levels and acts as a signaling molecule subject to the dedicated balance between ROS production and scavenging. Changes in oxygen concentrations affect ROS formation. When ROS levels exceed defense mechanisms, ROS causes oxidative stress. Increased ROS levels can also be a contributing factor to HIF stabilization during hypoxia and reoxygenation. In this review, we systemically review HIF activation and ROS formation in the brain during hypoxia and hypoxia/reoxygenation. We will then explore the literature describing how changes in HIF levels might provide pharmacological targets for effective ischaemic stroke treatment. HIF accumulation in the brain via HIF prolyl hydroxylase (PHD) inhibition is proposed as an effective therapy for ischaemia stroke due to its antioxidation and anti-inflammatory properties in addition to HIF pro-survival signaling. PHD is a key regulator of HIF levels in cells. Pharmacological inhibition of PHD increases HIF levels in normoxia (i.e., at 20.9% O2 level). Preconditioning with HIF PHD inhibitors show a neuroprotective effect in both in vitro and in vivo ischaemia stroke models, but post-stroke treatment with PHD inhibitors remains debatable. HIF PHD inhibition during reperfusion can reduce ROS formation and activate a number of cellular survival pathways. Given agents targeting individual molecules in the ischaemic cascade (e.g., antioxidants) fail to be translated in the clinic setting, thus far, HIF pathway targeting and thereby impacting entire physiological networks is a promising drug target for reducing the adverse effects of ischaemic stroke.

Keywords: brain; hypoxia; hypoxia inducible factor; prolyl hydroxylase; reactive oxygen species; reperfusion; stroke.

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Figures

FIGURE 1
FIGURE 1

Schematic diagram describing HIF pathway. At physioxia, HIFα is continuously produced and constantly hydroxylated by PHD1-3 at prolyl residue 402 and 564 of C- and N-terminal oxygen dependent degradation domains (CODD and NODD). The hydroxylated HIFα is then poly-ubiquitinated and is targeted for proteosomal degradation by an E3 ubiquitin ligase – the von Hippel-Lindau protein (pVHL) complex, resulting in rapid proteasome degradation. In addition, FIH hydroxylates an asparaginyl-residue in the C-terminal transcriptional domain of HIFα, inhibiting HIF mediated transcription; in hypoxia, activities of both PHD and FIH are reduced due to a lack of oxygen. HIFα accumulates in the cytoplasm, and enters the nucleus where HIFα dimerizes with HIF β to form the HIF molecule. The HIF complex is activated when interacting with the p300/CBP coactivators and then binds to HREs, leading to upregulating transcription of HIF downstream genes.

FIGURE 2
FIGURE 2

The interaction between ROS formation and HIF activation at different oxygen concentrations. (A) In hypoxia, HIF is stabilized and ROS formation is increased. While increased ROS levels in cells contribute to further stabilization of HIF, HIF stabilization can either reduce or increase ROS formation; (B) In physioxia, HIFα is continuously produced but is quickly degraded and HIF is not detectable, while ROS formation is minimum as pro-oxidant and anti-oxidant substances are balanced; and (C) In hyperoxia, ROS is elevated while HIF stabilization is prevented due to PHD inhibition. However, HIF stabilization can be induced through ROS while HIF stabilization can either reduce or increase ROS formation.

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