NADPH oxidase: a universal oxygen sensor?

doi:10.1016/S0891-5849(00)00320-8

Free Radical Biology and Medicine

Volume 29, Issue 5, 1 September 2000, Pages 416-424

https://doi.org/10.1016/S0891-5849(00)00320-8 Get rights and content

Abstract

NADPH oxidase is classically regarded as a key enzyme of neutrophils, where it is involved in the pathogenic production of reactive oxygen species. However, NADPH oxidase-like enzymes have recently been identified in non-neutrophil cells, supporting a separate role for NADPH-oxidase derived oxygen species in oxygen sensitive processes. This article reviews the current literature surrounding the potential role of NADPH oxidase in the oxygen sensing processes which underlie hypoxic pulmonary vasoconstriction, systemic vascular smooth muscle proliferation, carotid and airways chemoreceptor activation, erythropoietin gene expression, and oxytropic responses of plant cells.

Introduction

NADPH oxidase is recognized as one of the primary enzyme complexes involved in the antipathogen action of neutrophils and other phagocytic white cells. This action is mediated by the production of toxic forms of oxygen species, commonly referred to as reactive oxygen species (ROS) or active oxygen species (AOS), which are released into the forming phagosome (Fig. 1). The ability of NADPH oxidase to produce toxic oxygen radicals is vital for defense against infection, highlighted by sufferers of chronic granulomatous disease (CGD) who are susceptible to bacterial and fungal infection due to the lack of a functional enzyme [3].

Neutrophil NADPH oxidase utilizes NADPH as its substrate and catalyzes the one-electron reduction of oxygen to superoxide (Fig. 1). It is a membrane associated multisubunit enzyme, primarily located in the plasma membranes of cells. It consists in part of a flavocytochrome that is in fact a heterodimer. The smaller or α subunit is approximately 22 kDa, referred to as p22-phox, while the larger β subunit is approximately 91 kDa (gp91-phox) but is heavily glycosylated [4], [5]. In quiescent neutrophils no other polypeptides are associated with the membrane, but on activation three further polypeptides of 67 kDa (p67-phox), 47 kDa (p47-phox), and 40 kDa (p40-phox) are recruited. It is speculated that these cytosolic factors aid formation of the correct conformation of the flavocytochrome and are important for substrate binding and electron flow through the complex [6], [7]. Activity of the complex also requires the involvement of at least two G proteins. These are proteins that act as molecular switches, alternating between binding GDP in the inactive state and GTP in the active state. The G protein Rap1A has been found to copurify with the flavocytochrome [8], while the G protein p21^rac2 translocates to associate with the complex in a manner similar to that of the other cytosolic polypeptides [9], [10]. Normally p21^rac2 resides in the cytoplasm in association with the guanine nucleotide exchange inhibitor rhoGDI, but activation is catalyzed by GDS (a GDP dissociation stimulator protein) and GDP/GTP exchange. In some cell types the G protein is another member of the G protein superfamily, p21^rac1.

The redox activity of the NADPH oxidase complex appears to reside in the gp91-phox subunit. Here a FAD moeity is found along with two heme groups of different midpoint potentials −225mV and −265mV [11]. This cytochrome was originally assigned a single midpoint potential and is commonly referred to as cytochrome b₋₂₄₅ [12], although this would appear to be somewhat misleading in light of recent research. Alternate nomenclature refers to the cytochrome as cytochrome b₅₅₈ due to light absorbance of its α band.

Due to the catalytic mechanism of NADPH oxidase, electrons are passed through the enzyme complex from intracellular NADPH to extracellular molecular oxygen [13]. Consequently activation of NADPH oxidase is associated with a rapid depolarization of the membrane potential, attributed to the net outward movement of electrons [14]. The coproduced protons are initially retained intracellularly, which would result in further depolarization and a fall in pH if this occurred indefinitely. However after about a minute of stimulation, membrane depolarization reaches a steady state, even though superoxide is still being produced, indicating the movement of a compensatory charge into the external media. This is attributed to the delayed release of protons via an associated proton channel, conductance of which is voltage gated [15], [16]. The overall mechanism of superoxide generation by NADPH oxidase is shown in Fig. 2.

Section snippets

NADPH oxidase as an oxygen-sensing enzyme

Oxygen sensing is a ubiquitous process, vital throughout the plant and animal kingdoms. Plants display growth patterns that are determined in part by oxygen tension, and lower organisms and many mammalian systems also respond to the concentration of available oxygen. Hypoxic pulmonary vasoconstriction (HPV) is the physiological process by which pulmonary arteries and capillaries constrict in response to hypoxia, ensuring correct ventilation-perfusion matching. Although HPV is the most widely

NADPH oxidase in the pulmonary circulation

An NADPH oxidase has been proposed as the oxygen sensor postulated to control the contractile response of the pulmonary circulation to hypoxia. HPV ensures ventilation is matched with perfusion in the lung; vasoconstriction occurs in areas with low alveolar oxygen tensions, thus avoiding systemic hypoxemia. However HPV is also responsible for the increase in pulmonary vascular resistance present in numerous disease states characterized by global alveolar hypoxia, such as chronic obstructive

NADPH oxidase in the systemic circulation

While in the pulmonary circulation exposure to hypoxia results in vasoconstriction, in the systemic circulation a reduction in oxygen tension triggers vasodilation in order to increase blood flow to a hypoxic area. Although a large number of references concern the mechanism of HPV, the mechanism of systemic dilatation to acute hypoxia has received little attention. To our knowledge, to date no reports have studied the possible involvement of an NADPH oxidase in this systemic response. However,

NADPH oxidase and the carotid body

The carotid body is the structure responsible for the central detection of hypoxia. As with other hypoxic responses, the underlying mechanism whereby the carotid body is able to detect and transduce changes in PO₂ remains unknown. Data also supports an NADPH oxidase as a potential oxygen sensor in the carotid body.

Acker et al. [71] deduced from light absorbance spectra that an enzyme similar to neutrophil NADPH oxidase was present in the carotid body and showed that the NADPH oxidase inhibitor

NADPH oxidase and erythropoietin gene expression

NADPH oxidase has also been suggested as an oxygen sensor in the control of erythropoietin (epo) production, which is increased under hypoxic conditions [76]. Mechanisms similar to those postulated to govern HPV (hypothesis 2) have been proposed. Fandrey et al. [77] suggested that since H₂O₂ was demonstrated to inhibit epo gene expression in human hepatoma cells, high H₂O₂ concentrations under conditions of normoxia may suppress, and lower levels under conditions of hypoxia may allow, epo gene

NADPH oxidase and airway oxygen sensing

Pulmonary neuroepithelial bodies (NEB) are structurally similar to carotid chemoreceptors and are widely distributed throughout the human airways. Evidence suggests that these structures may function as hypoxia-sensitive airway receptors since hypoxia [86] and DPI [87] inhibit, and H₂O₂ [88] increases the outward potassium current of NEB. The presence of the gp91phox and p22phox subunits of NADPH oxidase have been identified in human and rabbit NEB [86], [87], [88], suggesting this enzyme as

NADPH oxidase and oxygen sensing in plants

Although most of the discussion in this review is centered on mammalian systems, plants also appear to show a sensitivity to oxygen, for example, in oxytropic responses [90]. Many plant tissues contain components of NADPH oxidase and are capable of generating ROS, either constitutively or in a stimulated manner. Therefore, is it possible that an NADPH oxidase type complex is involved in oxygen-sensing processes in plants too.

Generation of ROS is one of the early responses seen when a plant is

Conclusion

The existence of an enzyme similar to neutrophil NADPH oxidase in nonphagocytotic cells, and its ability to produce vasoactive and redox-active oxygen species in relation to oxygen concentrations, provide an extra dimension to the action of an enzyme that has long been recognized as a key structure in bacterial killing. Evidence supports a key role for this enzyme in the oxygen-sensing processes of pulmonary and systemic smooth muscle cells, which may have a profound influence on a number of

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¹: Richard Jones is a Postdoctoral Research Fellow in Respiratory Medicine at the University of Hull, where he heads the pulmonary circulation research group. He obtained his PhD from the University of Sheffield in 1999.

²: John Hancock is a Senior Lecturer in Molecular Cell Biology at the University of the West of England. He obtained his PhD in 1987 from the University of Bristol, moving to University of the West of England in 1993. He currently heads the free radical research group, whose interests include the generation and role of oxygen species in animals and plants.

³: Alyn Morice is Professor of Respiratory Medicine and Head of the Academic Department of Medicine, University of Hull. Previously a Lecturer in Medicine at the University of Cambridge, and Senior Lecturer then Reader in Medicine at The University of Sheffield, his main research interest is the role of hypoxia in control of pulmonary arterial tone.

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Review articleNADPH oxidase: a universal oxygen sensor?

Abstract

Introduction

Section snippets

NADPH oxidase as an oxygen-sensing enzyme

NADPH oxidase in the pulmonary circulation

NADPH oxidase in the systemic circulation

NADPH oxidase and the carotid body

NADPH oxidase and erythropoietin gene expression

NADPH oxidase and airway oxygen sensing

NADPH oxidase and oxygen sensing in plants

Conclusion

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biophys. J.

Eur. J. Pharmacol.

Chest

Pulm. Pharmacol. Ther.

Pulm. Pharmacol. Ther.

Gen. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

FEBS Lett.

Neurosci. Lett.

Respir. Physiol.

FEBS Lett.

Respir. Physiol.

Kidney Int.

FEBS Lett.

Phytochemistry

Biochim. Biophys. Acta

Phagocyte-generated oxygen metabolites and cellular injury

Lab. Invest.

Chemistry and cytotoxicity of reactive oxygen metabolites

Molecular characterization of the autosomal recessive forms of chronic granulotomous disease

Immunodefic. Rev.

Purified cytochrome b from human granulocyte plasma membrane is comprised of two polypeptides with relative molecular weights of 91,000 and 22,000

J. Clin. Invest.

Absence of both cytochrome b245 subunits from neutrophils in X-linked chronic granulomatous disease

Nature

The effect of the inhibitor diphenyleneiodonium on the superoxide-generating system of neutrophils. Specific labelling of a component polypeptide of the oxidase

Biochem. J.

Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1

Nature

Oxidation-reduction properties of the cytochrome b found in the plasma-membrane fraction of human neutrophils. A possible oxidase in the respiratory burst

Biochem. J.

Mechanism of the superoxide-producing oxidase of neutrophils. Oxygen is necessary for the fast reduction of cytochrome b245 by NADPH

Biochem. J.

The superoxide-generating NADPH oxidase of human neutrophils is electrogenic and associated with an H+ channel

Biochem. J.

A pH sensitive and voltage-dependent proton conductance in the plasma membrane of macrophages

J. Gen. Physiol.

O2 sensing is preserved in mice lacking the gp91phox subunit of NADPH oxidase

Proc. Natl. Acad. Sci. USA

Observations on the pulmonary arterial blood pressure in the cat

Acta Physiol. Scand.

Endothelin in the pulmonary circulation with special reference to hypoxic pulmonary vasoconstriction

Scand. Cardiovasc. J.

A redox-based O2 sensor in the rat pulmonary vasculature

Circ. Res.

Pulmonary artery NADPH-oxidase is activated in hypoxic pulmonary vasoconstriction

Am. J. Resp. Cell Mol. Biol.

Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle

Can. J. Physiol. Pharmacol.

Reactive oxygen–mediated contraction in pulmonary arterial smooth musclecellular mechanisms

Can. J. Physiol. Pharmacol.

Deoxyglucose and reduced glutathione mimic effects of hypoxia on potassium and calcium conductance in pulmonary artery cells

Am. J. Physiol.

Redox agents as a link between hypoxia and the responses of ionic channels in rabbit pulmonary vascular smooth muscle

Exp. Physiol.

Opposing effects of oxidants and antioxidants on potassium channel activity and tone in rat vascular tissue

Exp. Physiol.

Dithionate increases radical formation and decreases vasoconstriction in the lungevidence that dithionite does not mimic alveolar hypoxia

Circ. Res.

Toxic oxygen metabolites induce vasoconstriction and bronchoconstriction in isolated, plasma perfused rat lungs

Review article
NADPH oxidase: a universal oxygen sensor?

Absence of both cytochrome b₂₄₅ subunits from neutrophils in X-linked chronic granulomatous disease

Mechanism of the superoxide-producing oxidase of neutrophils. Oxygen is necessary for the fast reduction of cytochrome b₂₄₅ by NADPH

The superoxide-generating NADPH oxidase of human neutrophils is electrogenic and associated with an H⁺ channel

O₂ sensing is preserved in mice lacking the gp91phox subunit of NADPH oxidase

A redox-based O₂ sensor in the rat pulmonary vasculature