Activation and assembly of the NADPH oxidase: a structural perspective

Groemping, Yvonne; Rittinger, Katrin

doi:10.1042/bj20041835

Cited by 500 publications

(547 citation statements)

References 200 publications

(273 reference statements)

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“…In addition, enzymes such as lipoxygenases may also generate O 2 Ϫ . NOX has been implicated in several studies as the source of O 2 Ϫ in hypertension, atherosclerosis, and heart failure (5,11,17,32,46).The hypothesis of the present study is that the primary source of O 2 Ϫ during reverse flow stems from the NOX system. We tested this hypothesis by inhibiting various pathways while assessing the nitrite production and the degree of vasodilation.…”

mentioning

confidence: 70%

“…First, the saccharide chains that are attached to glycosylation sites found on the NOX homologue subunit which has six transmembrane helixes may be implicated (17,50). These chains may transmit reverse shear to the NOX homologue, causing increased O 2 Ϫ production.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Godbole AS, Lu X, Guo X, Kassab GS. NADPH oxidase has a directional response to shear stress. Am J Physiol Heart Circ Physiol 296: H152-H158, 2009. First published November 14, 2008 doi:10.1152/ajpheart.01251.2007.-Vessel regions with predilection to atherosclerosis have negative wall shear stress due to flow reversal. The flow reversal causes the production of superoxides (O 2 Ϫ ), which scavenge nitric oxide (NO), leading to a decrease in NO bioavailability and endothelial dysfunction. Here, we implicate NADPH oxidase as the primary source of O 2 Ϫ during full flow reversal. Nitrite production and the degree of vasodilation were measured in 46 porcine common femoral arteries in an ex vivo system. Nitrite production and vasodilation were determined before and after the inhibition of NADPH oxidase, xanthine oxidase, or mitochondrial oxidase. NADPH oxidase inhibition with gp91ds-tat or apocynin restored nitrite production and vasodilation during reverse flow. Xanthine oxidase inhibition increased nitrite production at the highest flow rate, whereas mitochondrial oxidase inhibition had no effect. These findings suggest that the NADPH oxidase system can respond to directional changes of flow and is activated to generate O 2 Ϫ during reverse flow in a dose-dependent fashion. These findings have important clinical implications for oxidative balance and NO bioavailability in regions of flow reversal in a normal and compromised cardiovascular system. superoxide; nitric oxide; oxidative balance; reduced nicotinamide adenine dinucleotide phosphate NITRIC OXIDE (NO) is released by endothelial cells to regulate blood vessel diameter acutely as well as to maintain long-term homeostatic conditions of the vessel wall (4,30). NO is produced in the endothelium from L-arginine by the enzyme endothelial NO synthase (eNOS) (4, 41) and is released in response to endothelial shear stress and other stimuli such as acetylcholine (4). Wall shear stress (WSS) has also been found to regulate the activity and expression of eNOS (34,40).Oscillatory and reverse WSS have negative effects on the endothelium due to superoxide (O 2 Ϫ ) production (14, 27, 28, 36, 52). It has been found that reverse flow in blood vessels causes reduced NO due to increased O 2 Ϫ production (36). Since NO is atheroprotective, regions of oscillatory and reverse WSS are more prone to atherosclerosis. Regions near branch points and curved vessels produce near-wall reverse flow (15,16).O 2 Ϫ can quickly inactivate NO, causing reduced NO bioavailability and endothelial dysfunction (9, 33). This endothelial dysfunction is implicated in atherosclerosis, hypertension, and heart failure (9,13,14,18,21). Reduced NO in the vessel wall impairs endothelium-dependent vasodilation, decreases inhibition of platelet and leukocyte adhesion, and is linked to the development of intimal hyperplasia (4, 21, 51). Our group has previously shown that NO production is reduced during reverse flow and that the addition of Tempol (an O 2 Ϫ scavenger) restored NO production in reverse flow to...

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confidence: 70%

Section: Discussionmentioning

confidence: 99%

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NADPH oxidase has a directional response to shear stress

Godbole¹,

Lu²,

Guo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…21,22 The production of superoxide by microglia occurs primarily by NADPH oxidase (NOX), of which several isoforms have been characterized. 23,24 Of note, glucose availability can be rate-limiting for NADPH production, and thus for superoxide production, and this provides a mechanism by which hyperglycemia can exacerbate injury during ischemia or inflammation. 25,26 Recent work has shown that microglia can potentiate injury to blood-brain barrier constituents (astrocytes and endothelial cells) via NOX-mediated superoxide in cell culture models of ischemia.…”

Section: Superoxide Productionmentioning

confidence: 99%

Microglial Activation in Stroke: Therapeutic Targets

2010

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Summary:Microglial activation is an early response to brain ischemia and many other stressors. Microglia continuously monitor and respond to changes in brain homeostasis and to specific signaling molecules expressed or released by neighboring cells. These signaling molecules, including ATP, glutamate, cytokines, prostaglandins, zinc, reactive oxygen species, and HSP60, may induce microglial proliferation and migration to the sites of injury. They also induce a nonspecific innate immune response that may exacerbate acute ischemic injury. This innate immune response includes release of reactive oxygen species, cytokines, and proteases. Microglial activation requires hours to days to fully develop, and thus presents a target for therapeutic intervention with a much longer window of opportunity than acute neuroprotection. Effective agents are now available for blocking both microglial receptor activation and the microglia effector responses that drive the inflammatory response after stroke. Effective agents are also available for targeting the signal transduction mechanisms linking these events. However, the innate immune response can have beneficial as well deleterious effects on outcome after stoke, and a challenge will be to find ways to selectively suppress the deleterious effects of microglial activation after stroke without compromising neurovascular repair and remodeling.

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“…The cytosolic components translocate to the membrane on neutrophil activation to form a functional oxidase complex with cytochrome b 558 . 60,61 To determine the level of expression of the NADPH oxidase subunits, quantitative Western immunoblot analysis was performed in WT and LFKO neutrophils. No significant difference in the levels of p22 phox , p40 phox , p47 phox , p67 phox , or gp91 phox were detected in the two groups ( Figure 5) indicating that the abnormal PMA-stimulated oxidative burst response observed in LFKO neutrophils is not because of altered expression of the NADPH oxidase subunits in these mice.…”

Section: Normal Expression Of Nadph Oxidase Components In Lfko Neutromentioning

confidence: 99%

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

Ward

Mendoza-Meneses

Park

et al. 2008

The American Journal of Pathology

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Lactoferrin (LF) is an iron-binding protein found in milk, mucosal secretions, and the secondary granules of neutrophils in which it is considered to be an important factor in the innate immune response against microbial infections. Moreover, LF deficiency in the secondary granules of neutrophils has long been speculated to contribute directly to the hypersusceptibility of specific granule deficiency (SGD) patients to severe, life-threatening bacterial infections. However, the exact physiological significance of LF in neutrophil-mediated host defense mechanisms remains controversial and has not yet been clearly established in vivo using relevant animal models. In this study, we used lactoferrin knockout (LFKO) mice to directly address the selective role of LF in the host defense response of neutrophils and to determine its contribution, if any, to the phenotype of SGD. Neutrophil maturation, migration, phagocytosis, granule release, and antimicrobial response to bacterial challenge were unaffected in LFKO mice. Interestingly, a stimulus-dependent defect in the oxidative burst response of LFKO neutrophils was observed in that normal activation was seen in response to opsonized bacteria whereas an impaired response was evident after phorbol myristate-13-acetate stimulation. Taken together, these results indicate that although LF deficiency alone is not a primary cause of the defects associated with SGD, this protein does play an immunomodulatory role in the oxidative burst response of neutrophils.

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Activation and assembly of the NADPH oxidase: a structural perspective

Cited by 500 publications

References 200 publications

NADPH oxidase has a directional response to shear stress

NADPH oxidase has a directional response to shear stress

Microglial Activation in Stroke: Therapeutic Targets

Stimulus-Dependent Impairment of the Neutrophil Oxidative Burst Response in Lactoferrin-Deficient Mice

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