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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of estrogen on neointimal formation in injured rat arteries has been reported to be a sexual dimorphic effect. Recently, it has been reported that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exhibit vasoprotective effects, which are independent of their cholesterol-lowering effects. In this study, we examined the gender differences of atorvastatin's effect on neointimal formation in balloon-injured rat arteries. Male and female Sprague Dawley rats underwent gonadectomy and balloon injury of the carotid artery. Ovariectomized female, as well as intact and castrated male, rats exhibited marked neointimal formation. Treatment with atorvastatin significantly reduced neointimal formation at day 14 (14 days after injury) and NADPH oxidase-dependent superoxide production at day 2 in ovariectomy, but not in intact and castrated males. In ovariectomized rats, 7 days of atorvastatin treatment from days -3 to 3 but not from days 7 to 14 suppressed neointimal formation at day 14. In this study, we showed that atorvastatin's effect on neointimal formation was female-specific and was more marked in ovariectomized female rats. NADPH oxidase-dependent superoxide production may be involved in the mechanism of the sexual dimorphic response seen in response to atorvastatin treatment. Furthermore, the results suggest the importance of treatment in the early phase after vascular injury.
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PMID:Gender difference of atorvastatin's vasoprotective effect in balloon-injured rat carotid arteries. 1705 30

The role of Leu505 of Nox2 on the NADPH oxidase activation process was investigated. An X-CGD PLB-985 cell line expressing the Leu505Arg Nox2 mutant was obtained, exactly mimicking the phenotype of a previously published X91+-CGD case. In a reconstituted cell-free system (CFS), NADPH oxidase and iodonitrotetrazolium (INT) reductase activities were partially maintained concomitantly with a partial cytosolic factors translocation to the plasma membrane. This suggests that assembly and electron transfer from NADPH occurred partially in the Leu505Arg Nox2 mutant. Moreover, in a simplified CFS using purified mutant cytochrome b558 and recombinant p67phox, p47phox, and Rac1proteins, we found that the Km for NADPH and for NADH was about three times higher than those of purified WT cytochrome b558, indicating that the Leu505Arg mutation induces a slight decrease of the affinity for NADPH and NADH. In addition, oxidase activity can be extended by increasing the amount of p67phox in the simplified CFS assay. However, the maximal reconstituted oxidase activity using WT purified cytochrome b558 could not be reached using mutant cytochrome b558. In a three-dimensional model of the C-terminal tail of Nox2, Leu505 appears to have a strategic position just at the entry of the NADPH binding site and at the end of the alpha-helical loop (residues 484-504), a potential cytosolic factor binding region. The Leu505Arg mutation seems to affect the oxidase complex activation process through alteration of cytosolic factors binding and more particularly the p67phox interaction with cytochrome b558, thus affecting NADPH access to its binding site.
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PMID:Leu505 of Nox2 is crucial for optimal p67phox-dependent activation of the flavocytochrome b558 during phagocytic NADPH oxidase assembly. 1706 Mar 62

Ferredoxin:NADP oxidoreductases (FNRs) constitute a family of flavoenzymes that catalyze the exchange of reducing equivalents between one-electron carriers and the two-electron-carrying NADP(H). The main role of FNRs in cyanobacteria and leaf plastids is to provide the NADPH for photoautotrophic metabolism. In root plastids, a distinct FNR isoform is found that has been postulated to function in the opposite direction, providing electrons for nitrogen assimilation at the expense of NADPH generated by heterotrophic metabolism. A multiple gene family encodes FNR isoenzymes in plants, whereas there is only one FNR gene (petH) in cyanobacteria. Nevertheless, we detected two FNR isoforms in the cyanobacterium Synechocystis sp. strain PCC6803. One of them (FNR(S) approximately 34 kDa) is similar in size to the plastid FNR and specifically accumulates under heterotrophic conditions, whereas the other one (FNR(L) approximately 46 kDa) contains an extra N-terminal domain that allows its association with the phycobilisome. Site-directed mutants allowed us to conclude that the smaller isoform, FNR(S), is produced from an internal ribosome entry site within the petH ORF. Thus we have uncovered a mechanism by which two isoforms are produced from a single gene, which is, to our knowledge, novel in photosynthetic bacteria. Our results strongly suggest that FNR(L) is an NADP(+) reductase, whereas FNR(S) is an NADPH oxidase.
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PMID:A second isoform of the ferredoxin:NADP oxidoreductase generated by an in-frame initiation of translation. 1711 80

Lysophosphatidic acid (LPA), a product generated during oxidative modification of low-density lipoprotein (LDL) and a major lipid extracted from human atherosclerotic plaques, has been shown to elicit smooth muscle cell (SMC) proliferation and inflammation, thereby being involved in atherogenesis. Recently, statins, an inhibitor of 3-hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase, have been reported to reduce the risk of cardiovascular events and slows the progression of atherosclerosis, at least partly, via pleiotropic effects. However, the effect of statin on the LPA-signaling in SMCs remains to be elucidated. In this study, we investigated whether and how pitavastatin could inhibit the LPA-induced proliferation and monocyte chemoattractant protein-1 (MCP-1) expression in cultured human aortic SMCs. LPA dose-dependently increased intracellular reactive oxygen species (ROS) generation in SMCs, which was blocked by diphenylene iodonium (DPI), an inhibitor of NADPH oxidase or pitavastatin. The anti-oxidative property of pitavastatin was prevented by simultaneous treatment of geranylgeranyl pyrophosphate. Furthermore, overexpression of dominant negative Rac-1 mutant was found to inhibit the LPA-induced ROS generation in SMCs. LPA induced Rac-1 activation in SMCs, which was suppressed by pitavastatin or LPA receptor antagonist. Pitavastatin, DPI, and an anti-oxidant N-acetylcysteine inhibited the LPA-induced proliferation and MCP-1 gene expression in SMCs. These results suggest that pitavastatin could block the LPA-induced proliferation and MCP-1 expression in SMCs by suppressing Rac-1-mediated NADPH oxidase-dependent ROS generation. Our present study provides a novel beneficial aspect of pitavastatin; pitavastatin may act as a blocker of the LPA-signaling in SMCs.
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PMID:Pitavastatin inhibits lysophosphatidic acid-induced proliferation and monocyte chemoattractant protein-1 expression in aortic smooth muscle cells by suppressing Rac-1-mediated reactive oxygen species generation. 1717 55

Pulmonary fibrosis is one of the most severe consequences of exposure to paraquat, an herbicide that causes rapid alveolar inflammation and epithelial cell damage. Paraquat is known to induce toxicity in cells by stimulating oxygen utilization via redox cycling and the generation of reactive oxygen intermediates. However, the enzymatic activity mediating this reaction in lung cells is not completely understood. Using self-referencing microsensors, we measured the effects of paraquat on oxygen flux into murine lung epithelial cells. Paraquat (10-100 microm) was found to cause a 2-4-fold increase in cellular oxygen flux. The mitochondrial poisons cyanide, rotenone, and antimycin A prevented mitochondrial- but not paraquat-mediated oxygen flux into cells. In contrast, diphenyleneiodonium (10 microm), an NADPH oxidase inhibitor, blocked the effects of paraquat without altering mitochondrial respiration. NADPH oxidases, enzymes that are highly expressed in lung epithelial cells, utilize molecular oxygen to generate superoxide anion. We discovered that lung epithelial cells possess a distinct cytoplasmic diphenyleneiodonium-sensitive NAD(P)H:paraquat oxidoreductase. This enzyme utilizes oxygen, requires NADH or NADPH, and readily generates the reduced paraquat radical. Purification and sequence analysis identified this enzyme activity as thioredoxin reductase. Purified paraquat reductase from the cells contained thioredoxin reductase activity, and purified rat liver thioredoxin reductase or recombinant enzyme possessed paraquat reductase activity. Reactive oxygen intermediates and subsequent oxidative stress generated from this enzyme are likely to contribute to paraquat-induced lung toxicity.
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PMID:Paraquat increases cyanide-insensitive respiration in murine lung epithelial cells by activating an NAD(P)H:paraquat oxidoreductase: identification of the enzyme as thioredoxin reductase. 1722 25

Cholesterol metabolism is particularly active in malignant, proliferative cells, whereas cholesterol starvation has been shown to inhibit cell proliferation. Inhibition of enzymes involved in cholesterol biosynthesis at steps before the formation of 7-dehydrocholesterol has been shown to selectively affect cell cycle progression from G(2) phase in human promyelocytic HL-60 cells. In the present work, we explored whether cholesterol starvation by culture in cholesterol-free medium and treatment with different distal cholesterol biosynthesis inhibitors induces differentiation of HL-60 cells. Treatment with SKF 104976, an inhibitor of lanosterol 14-alpha demethylase, or with zaragozic acid, which inhibits squalene synthase, caused morphologic changes alongside respiratory burst activity and expression of cluster of differentiation antigen 11c (CD11c) but not cluster of differentiation antigen 14. These effects were comparable to those produced by all-trans retinoic acid, which induces HL-60 cells to differentiate following a granulocyte lineage. In contrast, they differed from those produced by vitamin D(3), which promotes monocyte differentiation. The specificity of the response was confirmed by addition of cholesterol to the culture medium. Treatment with PD 98059, an inhibitor of extracellular signal-regulated kinase, abolished both the activation of NADPH oxidase and the expression of the CD11c marker. In sharp contrast, BM 15766, which inhibits sterol Delta(7)-reductase, failed to induce differentiation or arrest cell proliferation. These results show that changes in the sterol composition may trigger a differentiation response and highlight the potential of cholesterol pathway inhibition as a possible tool for use in cancer therapy.
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PMID:Cholesterol starvation induces differentiation of human leukemia HL-60 cells. 1740 48

Bundle sheath chloroplasts of NADP-malic enzyme (NADP-ME) type C4 species have a high demand for ATP, while being deficient in linear electron flow and oxidation of water by photosystem II (PSII). To evaluate electron donors to photosystem I (PSI) and possible pathways of cyclic electron flow (CEF1) in isolated bundle sheath strands of maize (Zea mays L.), an NADP-ME species, light-induced redox kinetics of the reaction center chlorophyll of PSI (P700) were followed under aerobic conditions. Donors of electrons to CEF1 are needed to compensate for electrons lost from the cycle. When stromal electron donors to CEF1 are generated during pre-illumination with actinic light (AL), they retard the subsequent rate of oxidation of P700 by far-red light. Ascorbate was more effective than malate in generating stromal electron donors by AL. The generation of stromal donors by ascorbate was inhibited by DCMU, showing ascorbate donates electrons to the oxidizing side of PSII. The inhibitors of NADPH dehydrogenase (NDH), amytal and rotenone, accelerated the oxidation rate of P700 by far-red light after AL, indicating donation of electrons to the intersystem from stromal donors via NDH. These inhibitors, however, did not affect the steady-state level of P700+ under AL, which represents a balance of input and output of electrons in P700. In contrast, antimycin A, the inhibitor of the ferredoxin-plastoquinone reductase-dependent CEF1, substantially lowered the level of P700+ under AL. Thus, the primary pathway of ATP generation by CEF1 may be through ferredoxin-plastoquinone, while function of CEF1 via NDH may be restricted by low levels of ferredoxin-NADP reductase. NDH may contribute to redox poising of CEF1, or function to generate ATP in linear electron flow to O2 via PSI, utilizing NADPH generated from malate by chloroplastic NADP-ME.
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PMID:Analysis of donors of electrons to photosystem I and cyclic electron flow by redox kinetics of P700 in chloroplasts of isolated bundle sheath strands of maize. 1755 45

Synaptic plasma membranes (SPMV) decrease the steady state ascorbate free radical (AFR) concentration of 1mM ascorbate in phosphate/EDTA buffer (pH 7), due to AFR recycling by redox coupling between ascorbate and the ubiquinone content of these membranes. In the presence of NADH, but not NADPH, SPMV catalyse a rapid recycling of AFR which further lower the AFR concentration below 0.05 microM. These results correlate with the nearly 10-fold higher NADH oxidase over NADPH oxidase activity of SPMV. SPMV has NADH-dependent coenzyme Q reductase activity. In the presence of ascorbate the stimulation of the NADH oxidase activity of SPMV by coenzyme Q(1) and cytochrome c can be accounted for by the increase of the AFR concentration generated by the redox pairs ascorbate/coenzyme Q(1) and ascorbate/cytochrome c. The NADH:AFR reductase activity makes a major contribution to the NADH oxidase activity of SPMV and decreases the steady-state AFR concentration well below the micromolar concentration range.
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PMID:Reduction of ascorbate free radical by the plasma membrane of synaptic terminals from rat brain. 1796 86

The C-terminal tail (CT) of neuronal nitric oxide synthase (nNOS) is a regulatory element that suppresses nNOS activities in the absence of bound calmodulin (CaM). A crystal structure of the nNOS reductase domain (nNOSr) (Garcin, E. D., Bruns, C. M., Lloyd, S. J., Hosfield, D. J., Tiso, M., Gachhui, R., Stuehr, D. J., Tainer, J. A., and Getzoff, E. D. (2004) J. Biol. Chem. 279, 37918-37927) revealed how the first half of the CT interacts with nNOSr and thus provided a template for detailed studies. We generated truncation mutants in nNOS and nNOSr to test the importance of 3 different regions of the CT. Eliminating the terminal half of the CT (all residues from Ile1413 to Ser1429), which is invisible in the crystal structure, had almost no impact on NADP+ release, flavin reduction, flavin autoxidation, heme reduction, reductase activity, or NO synthesis activity, but did prevent an increase in FMN shielding that normally occurs in response to NADPH binding. Additional removal of the CT alpha-helix (residues 1401 to 1412) significantly increased the NADP+ release rate, flavin autoxidation, and NADPH oxidase activity, and caused hyper-deshielding of the FMN cofactor. These effects were associated with increased reductase activity and slightly diminished heme reduction and NO synthesis. Further removal of residues downstream from Gly1396 (a full CT truncation) amplified the aforementioned effects and in addition altered NADP+ interaction with FAD, relieved the kinetic suppression on flavin reduction, and further diminished heme reduction and NO synthesis. Our results reveal that the CT exerts both multifaceted and regiospecific effects on catalytic activities and related behaviors, and thus provide new insights into mechanisms that regulate nNOS catalysis.
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PMID:Versatile regulation of neuronal nitric oxide synthase by specific regions of its C-terminal tail. 1802 Apr 58

Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II-dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22(phox)) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.
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PMID:Attenuation of NADPH oxidase activation and glomerular filtration barrier remodeling with statin treatment. 1817 55


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