Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NO is known to induce expression of heme oxygenase-1, an antioxidant enzyme in blood vessels. We tested whether NO might modulate the endothelial NADPH oxidase function via heme oxygenase-1. In human microvascular endothelial cells, the NO donor DETA-NONOate (0.1 to 1 mmol/L) strongly induced expression of heme oxygenase-1 but not Cu/Zn superoxide dismutase. This was associated with a reduction of the superoxide-generating capacity of NADPH oxidase, an effect that depended on de novo gene transcription and heme oxygenase-1 activity. Activation of NADPH oxidase by tumor necrosis factor (TNF) alpha increased generation of reactive oxygen species. DETA-NONOate alone had little effect on TNF-stimulated reactive oxygen species, but it enhanced the TNF response when: (1) heme oxygenase-1 expression was blocked with specific small-interfering RNA; (2) heme oxygenase-1 activity was blocked by zinc-protoporphyrin; or (3) NADPH oxidase activity was blocked by diphenyleneiodonium. Moreover, the heme oxygenase-1 end product bilirubin directly inhibited fully functional NADPH oxidase and seemed to interrupt the assembly and activation of the oxidase. In conclusion, NO may modulate superoxide production by NADPH oxidase in human vascular endothelial cells, at least partly by inducing heme oxygenase-1. Our results indicate that suppression of NADPH oxidase-dependent reactive oxygen species formation may represent a novel mechanism underlying the cardiovascular protective actions of heme oxygenase-1 and bilirubin.
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PMID:NO modulates NADPH oxidase function via heme oxygenase-1 in human endothelial cells. 1698 56

Exposure of human umbilical endothelial cells (ECs) to cigarette smoke extract (CSE) activated the NADPH-oxidase enzyme and increased the production of superoxide (O-2) as well as reactive oxygen species (ROS). CSE also inhibited the prostacyclin (PGI2) formation by ECs. Preincubation of ECs with diphenylene iodonium (DPI), the inhibitor of NADPH oxidase, blocked the increase of O-2 production, but neither lowered the ROS level nor prevented the inhibition of PGI2 formation in CSE-treated cells. Preincubation of ECs with a medium supplemented with 1 mM vitamin C did not decrease, but rather increased the O-2 production in CSE-treated cells. However, adding 1 mM glutathione (GSH) to vitamin C decreased the O-2 production, indicating that vitamin C was overwhelmed by the prooxidant in CS, and GSH enhanced the recycling process and spared vitamin C. The ROS level remained high in CSE-treated cells even after preincubation with vitamin C or vitamin C + GSH compared to the control cells. These results are discussed in light of the possible decrease of antioxidant enzyme activities in CSE-treated cells and the increase of cellular hydrogen peroxide (H2O2) generated from the CSE, which cause an imbalance between oxidizing species and the antioxidants producing oxidative stress in CSE-treated cells. These results demonstrate that CSE has a direct inhibitory effect on PGI2 formation and enhances the level of ROS in CSE-treated ECs, regardless of the activation of NADPH-oxidase.
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PMID:Inhibition of prostacyclin release by cigarette smoke extract in endothelial cells is not related to enhanced superoxide generation and NADPH-oxidase activation. 1707 61

Reactive oxygen species are important mediators of injury in acute renal failure (ARF). Although polymorphisms that affect key pro- and antioxidant enzymes might alter the susceptibility to oxidative stress-mediated injury, the use of genetic epidemiology for the study of oxidative stress-related genes has received little attention in ARF. The relationship of single-nucleotide polymorphisms in the coding region (C to T substitution at position +242) of the pro-oxidant enzyme NADPH oxidase p22phox subunit gene and in the promoter region (C to T substitution at position -262) of the antioxidant enzyme catalase gene to adverse clinical outcomes was evaluated prospectively in a cohort of 200 hospitalized patients with established ARF of mixed cause and severity. Genomic DNA was extracted from peripheral blood leukocytes and analyzed with a restriction fragment length polymorphism PCR method. Genotype-phenotype associations were characterized by measuring circulating nitrotyrosine and catalase activity. Observed and expected genotype frequencies were not significantly different, and overall baseline characteristics were not significantly different according to the various genotype groups. A genotype-phenotype association was demonstrable between the NADPH oxidase p22phox genotypes and plasma nitrotyrosine level (P = 0.06), as well as between the catalase genotypes and whole-blood catalase activity (P < 0.001). Compared with the NADPH oxidase p22phox CC genotype group, the T-allele group had a higher cumulative probability of remaining hospitalized (P = 0.03). Compared with the NADPH oxidase p22phox CC genotype, the T-allele carrier state was associated with 2.1-fold higher odds for dialysis requirement or hospital death (P = 0.01). This association persisted with 2.0- to 2.2-fold higher odds for this composite outcome after adjustment for race; gender; age; and the Acute Physiology and Chronic Health Evaluation II score (P = 0.03), the Multiple Organ Failure score (P = 0.01), or presence of sepsis (P = 0.02). The polymorphism in the gene that encodes the NADPH oxidase p22phox subunit at position +242 is associated with dialysis requirement or hospital death among patients with ARF. Larger studies are needed to confirm these relationships.
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PMID:NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure. 1718 82

The effects of excess copper (Cu) on the accumulation of hydrogen peroxide (H2O2) and antioxidant enzyme activities in roots of the Cu accumulator Elsholtzia haichowensis Sun were investigated. Copper at 100 and 300 microM significantly increased the concentrations of malondialdehyde and H2O2, and the activities of catalase (E.C. 1.11.1.6), ascorbate peroxidase (E.C. 1.11.1.11), guaiacol peroxidase (GPOD, E.C. 1.11.1.7) and superoxide dismutase (SOD, E.C. 1.15.1.1). Isoenzyme pattern and inhibitor studies showed that, among SOD isoforms, only copper-zinc superoxide dismutase (CuZn-SOD) increased. Excess Cu greatly increased the accumulation of superoxide anion (O2 (.-)) and H2O2 in E. haichowensis roots. This study also provides the first cytochemical evidence of an accumulation of H2O2 in the root cell walls as a consequence of Cu treatments. Experiments with diphenyleneiodonium as an inhibitor of NADPH oxidase, 1,2-dihydroxybenzene-3,5-disulphonic acid as an O2 (.-) scavenger, and N-N-diethyldithiocarbamate as an inhibitor of SOD showed that the source of H2O2 in the cell walls could partially be NADPH oxidase. The enzyme can use cytosolic NADPH to produce O2 (.-), which rapidly dismutates to H2O2 by SOD. Apoplastic GPOD and CuZn-SOD activities were induced in roots of E. haichowensis with 100 microM Cu suggesting that these two antioxidant enzymes may be responsible for H2O2 accumulation in the root apoplast.
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PMID:Excess copper induces accumulation of hydrogen peroxide and increases lipid peroxidation and total activity of copper-zinc superoxide dismutase in roots of Elsholtzia haichowensis. 1790 54

The aim of this study was to provide new insights into the role of angiotensin II and arterial pressure in the regulation of antioxidant enzyme activities in a renovascular model of cardiac hypertrophy. For this purpose, aortic coarcted rats were treated with losartan or minoxidil for 7 days. Angiotensin II induced cardiac hypertrophy and oxidative stress via Nox4, p22(phox) and p47(phox), which are components of the NAD(P)H oxidase. Antioxidant enzymes were regulated by arterial pressure and were not implicated in cardiac hypertrophy. Heme oxygenase-1, the rate-limiting enzyme in heme catabolism, behaved as a catalase and glutathione peroxidase, and is regulated by arterial pressure. In summary, the present report indicates that cardiac hypertrophy, induced by renovascular hypertension, depends on angiotensin II through reactive oxygen species and is not prevented by the action of antioxidant enzymes.
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PMID:Angiotensin II regulates cardiac hypertrophy via oxidative stress but not antioxidant enzyme activities in experimental renovascular hypertension. 1836 53

Expression of the repair enzyme protein L-isoaspartyl methyltransferase (PIMT) has been reported to play important roles in brain. However, little is known about the regulation of PIMT expression following protein damage by oxidation in brain. Phenylarsine oxide (PAO) is an arsenical compound that alters proteins by forming disulfide bond with vicinal cysteinyl residues. Here we report that PIMT was rapidly up-regulated by PAO in U-87 human astroglioma cells. We also confirmed that PIMT up-regulation by PAO was mediated by the reaction with vicinal cysteines. Furthermore, we showed that PIMT induction by PAO was dependent on formation of reactive oxygen species (ROS). Crucially, both ROS formation and PIMT induction by PAO were inhibited by antioxidant N-acetyl-L-cysteine and NADPH oxidase inhibitor diphenyleneiodonium chloride. Importantly, down-regulation of PIMT by siRNA strikingly enhanced PAO-induced ROS. Together, these results highlight that PIMT expression is regulated by ROS and could primarily act as an antioxidant enzyme.
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PMID:Reactive oxygen species generated by thiol-modifying phenylarsine oxide stimulate the expression of protein L-isoaspartyl methyltransferase. 1840 33

Oxidative stress mediated by hyperglycaemia-induced generation of reactive oxygen species (ROS) contributes significantly to the development and progression of diabetes and related vascular complications. NAD(P)H oxidase has been implicated as the major source of ROS generation in the vasculature in response to high glucose and advanced glycation end-products. Sustained activation of NAD(P)H oxidase in diabetes may diminish intracellular levels of NADPH, an essential cofactor for endothelial NO synthase (eNOS) and several antioxidant systems. Recent evidence suggests that basal ROS production via NAD(P)H oxidase may upregulate antioxidant enzyme defenses via redox signalling. Thus, NAD(P)H oxidase may serve as a double-edged sword, with transient activation providing a feedback defense against excessive ROS generation through the activation of receptor tyrosine kinases and the redox-sensitive Nrf2-Keap1 signalling pathway. Overproduction of ROS leads to eNOS uncoupling, mitochondrial dysfunction, and impaired antioxidant defenses owing to depletion of intracellular NADPH. Given the largely negative outcome of antioxidant therapy in the treatment of diabetic complications, targeting the redox-sensitive transcription factor Nfr2 may provide an effective strategy to restore antioxidant defenses in diabetes.
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PMID:Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. 1917 52

Reactive oxygen species increase in the cardiovascular system during hypertension and in response to angiotensin II. Because mitochondria contribute to reactive oxygen species generation, we sought to investigate the role of thioredoxin 2, a mitochondria-specific antioxidant enzyme. Mice were created with overexpression of human thioredoxin 2 (Tg(hTrx2) mice) and backcrossed to C57BL/6J mice for > or =6 generations. Twelve-week-old male Tg(hTrx2) or littermate wild-type mice were made hypertensive by infusion of angiotensin II (400 ng/kg per minute) for 14 days using osmotic minipumps. Systolic arterial blood pressure was not different between Tg(hTrx2) and wild-type animals under baseline conditions (101+/-1 respective 102+/-1 mm Hg). The angiotensin II-induced hypertension in wild-type mice (145+/-2 mm Hg) was significantly attenuated in Tg(hTrx2) mice (124+/-1 mm Hg; P<0.001). Aortic endothelium-dependent relaxation was significantly reduced in wild-type mice after angiotensin II infusion but nearly unchanged in transgenic mice. Elevated vascular superoxide and hydrogen peroxide levels, as well as expression of NADPH oxidase subunits in response to angiotensin II infusion, were significantly attenuated in Tg(hTrx2) mice. Mitochondrial superoxide anion levels were augmented after angiotensin II infusion in wild-type mice, and this was blunted in Tg(hTrx2) mice. Angiotensin II infusion significantly increased myocardial superoxide formation, heart weight, and cardiomyocyte size in wild-type but not in Tg(hTrx2) mice. These data indicate a major role for mitochondrial thioredoxin 2 in the development of cardiovascular alterations and hypertension during chronic angiotensin II infusion. Thioredoxin 2 may represent an important therapeutic target for the prevention and treatment of hypertension and oxidative stress.
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PMID:Attenuation of angiotensin II-induced vascular dysfunction and hypertension by overexpression of Thioredoxin 2. 1950 95

Recently, we reported that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) contribute to aberrant responses in pulmonary resistance arteries (PRAs) of piglets exposed to 3 days of hypoxia (Am J Physiol Lung Cell Mol Physiol 295: L881-L888, 2008). An objective of the present study was to determine whether NOX-derived ROS also contribute to altered PRA responses at a more advanced stage of pulmonary hypertension, after 10 days of hypoxia. We further wished to advance knowledge about the specific NOX and antioxidant enzymes that are altered at early and later stages of pulmonary hypertension. Piglets were raised in room air (control) or hypoxia for 3 or 10 days. Using a cannulated artery technique, we found that treatments with agents that inhibit NOX (apocynin) or remove ROS [an SOD mimetic (M40403) + polyethylene glycol-catalase] diminished responses to ACh in PRAs from piglets exposed to 10 days of hypoxia. Western blot analysis showed an increase in expression of NOX1 and the membrane fraction of p67phox. Expression of NOX4, SOD2, and catalase were unchanged, whereas expression of SOD1 was reduced, in arteries from piglets raised in hypoxia for 3 or 10 days. Markers of oxidant stress, F(2)-isoprostanes, measured by gas chromatography-mass spectrometry, were increased in PRAs from piglets raised in hypoxia for 3 days, but not 10 days. We conclude that ROS derived from some, but not all, NOX family members, as well as alterations in the antioxidant enzyme SOD1, contribute to aberrant PRA responses at an early and a more progressive stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.
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PMID:NADPH oxidases and reactive oxygen species at different stages of chronic hypoxia-induced pulmonary hypertension in newborn piglets. 1959 58

Using in vitro systems, numerous authors have cited the sensitivity of pollen tube growth to high temperature as a major cause of low yields for crops with valuable reproductive structures. We investigated the hypothesis that in vivo fertilization efficiency would be negatively affected by heat stress-induced changes in energy reserves and calcium-mediated oxidative status in the pistil. Gossypium hirsutum plants exposed to optimal (30/20 degrees C) or high day temperature (38/20 degrees C) conditions during flowering were analyzed for fertilization efficiency via UV microscopic observation of pollen tube-containing ovules and for soluble carbohydrates, adenosine triphosphate (ATP), calcium, antioxidant enzyme activity and NADPH oxidase (NOX; EC 1.6.3.1) activity in the pistil. Leaf measurements included gas exchange, chlorophyll content, quantum efficiency and ATP content of the subtending leaf on the day of anthesis. In the pistil fertilization efficiency, soluble carbohydrates, ATP content and NOX activity declined significantly, whereas water soluble calcium and glutathione reductase (EC 1.8.1.7) activity increased, and superoxide dismutase (EC 1.15.1.1) activity remained unchanged. In leaves, heat stress decreased photosynthesis, quantum efficiency and chlorophyll content, but increased stomatal conductance. We conclude that decreased source leaf activity either inhibits pollen development, tube growth through the style or guidance to the ovules as a result of an insufficient energy supply to the developing pistil. We further conclude that a calcium-augmented antioxidant response in heat-stressed pistils interferes with enzymatic superoxide production needed for normal pollen tube growth and fertilization of the ovule.
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PMID:Heat stress-induced limitations to reproductive success in Gossypium hirsutum. 1965 31


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