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)

NADPH oxidase is the major source of superoxide production in cardiovascular tissues. We and others reported that PG (prostaglandin) F2alpha, PDGF (platelet-derived growth factor) and angiotensin II cause hypertrophy of vascular smooth muscle cells by induction of NOX1 (NADPH oxidase 1), a catalytic subunit of NADPH oxidase. We found DPI (diphenylene iodonium), an inhibitor of flavoproteins, including NADPH oxidase itself, almost completely suppressed induction of NOX1 mRNA by PGF2alpha or PDGF in a rat vascular smooth muscle cell line, A7r5. Exploration into the site of action of DPI using various inhibitors suggested the involvement of mitochondrial oxidative phosphorylation in PGF2alpha- or PDGF-induced increase in NOX1 mRNA. In a luciferase reporter assay, activation of the CRE (cAMP-response element)-dependent gene transcription by PGF2alpha was attenuated by oligomycin, an inhibitor of mitochondrial F(o)F1-ATPase. Oligomycin and other mitochondrial inhibitors also suppressed PGF2alpha-induced phosphorylation of ATF (activating transcription factor)-1, a transcription factor of the CREB (CRE-binding protein)/ATF family. Silencing of the ATF-1 gene by RNA interference significantly reduced the induction of NOX1 by PGF2alpha or PDGF, while overexpression of ATF-1 recovered NOX1 induction suppressed by oligomycin. Taken together, ATF-1 may play a pivotal role in the up-regulation of NOX1 in rat vascular smooth muscle cells.
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PMID:Essential role of ATF-1 in induction of NOX1, a catalytic subunit of NADPH oxidase: involvement of mitochondrial respiratory chain. 1549 Dec 78

It is well established that growth-factor-induced reactive oxygen species (ROS) act as second messengers in cell signaling. We have previously reported that betaPix, a guanine nucleotide exchange factor for Rac, interacts with NADPH oxidase 1 (Nox1) leading to EGF-induced ROS generation. Here, we report the identification of the domains of Nox1 and betaPix responsible for the interaction between the two proteins. GST pull-down assays show that the PH domain of betaPix binds to the FAD-binding region of Nox1. We also show that overexpression of the PH domain of betaPix results in inhibition of superoxide anion generation in response to EGF. Additionally, NADPH oxidase Organizer 1 (NoxO1) is shown to interact with the NADPH-binding region of Nox1. These results suggest that the formation of the complex consisting of Nox1, betaPix, and NoxO1 is likely to be a critical step in EGF-induced ROS generation.
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PMID:Molecular interaction of NADPH oxidase 1 with betaPix and Nox Organizer 1. 1632 88

NADPH oxidase is implicated in the pathogenesis of various cardiovascular disorders. In vascular smooth muscle cells (VSMC), expression of NOX1 (NADPH oxidase 1), a catalytic subunit of NADPH oxidase, is low and is induced upon stimulation by vasoactive factors, while it is abundantly expressed in colon epithelial cells. To clarify the regulatory mechanisms underlying such cell-specific expression, the upstream regions directing transcription of the NOX1 gene were explored. In P53LMACO1 cells, a cell line originated from mouse VSMCs, two novel Nox1 mRNA species, the c- and f-type, were isolated. These transcripts contained 5'-untranslated regions that differed from the colon type mRNA (a-type) and encoded an additional N-terminal peptide of 28 amino acids. When these transcripts were fused to the c-myc tag and expressed in human embryonic kidney 293 cells, a fraction of translated proteins demonstrated the size containing the additional peptide. Proteins encoded by the c- and f-type mRNAs exhibited superoxide-producing activities equivalent to the activity of the a-type form. The a-type mRNA was expressed in the colon and in the intact aorta, whereas the c-type mRNA was detected in the primary cultured VSMCs migrated from aortic explants, in vascular tissue of a wire-injury model and in the thoracic aorta of mice infused with angiotensin II. The promoter region of the c-type mRNA exhibited transcriptional activity in P53LMACO1 cells, but not in MCE301 cells, a mouse colon epithelial cell line. These results suggest that expression of the Nox1 gene is regulated by alternative promoters and that the novel c-type transcript is induced under phenotypic modulation of VSMCs.
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PMID:Novel transcripts of Nox1 are regulated by alternative promoters and expressed under phenotypic modulation of vascular smooth muscle cells. 1672 59

The tonic contraction of human and guinea pig gallbladder (GB) is dependent on basal levels of PGE(2) and thromboxane A(2) (TxA(2)). The pathway involved in the genesis of these prostaglandins has not been elucidated. We aimed to examine the source of reactive oxygen species (ROS) and whether they contribute to the genesis of GB tonic contraction by generating basal prostaglandin levels. Tonic contraction was studied in human and guinea pig GB muscle strips treated with ROS scavengers (Tiron and catalase), apocynin (an inhibitor of NADPH oxidase), and NOX-1 small interference RNA (siRNA). The subunits of NADPH oxidase and their functional roles were determined with specific antibodies in GB muscle cells. ROS scavengers reduced the GB tonic contraction and H(2)O(2) and PGE(2) levels. Apocynin also inhibited the tonic contraction. Antibodies against subunits of NADPH oxidase present in GB muscle cells lowered H(2)O(2) and PGE(2) levels. NOX-1 siRNA transfection reduced the tonic contraction, NOX-1 expression, and levels of H(2)O(2) and PGE(2). Tiron and apocynin inhibited the expected increase in tension and H(2)O(2) levels induced by stretching of muscle strips. H(2)O(2) increased the levels of PGE(2) and TxA(2) by increasing platelet-activating factor-like lipids that phosphorylate p38 and cPLA(2) sequentially. H(2)O(2) generated by NADPH oxidase participates in a signal transduction pathway that maintains the GB tonic contraction by activating PAF, p38, and cPLA(2) to generate prostaglandins.
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PMID:Reactive oxygen species are messengers in maintenance of human and guinea pig gallbladder tonic contraction. 1862 97

The activity of NADPH oxidase (NOX) is blocked by nitric oxide (NO). Hydrogen sulfide (H(2)S) is also produced by blood vessels. It is reasonable to suggest that H(2)S may have similar actions to NO on NOX. In order to test this hypothesis, the effect of sodium hydrosulfide (NaHS) on O(2)(-) formation, the expression of NOX-1 (a catalytic subunit of NOX) and Rac(1) activity (essential for full NOX activity) in isolated vascular smooth muscle cells (hVSMCs) was investigated. hVSMCs were incubated with the thromboxane A(2) analogue U46619 +/- NaHS for 1 or 16 h, and O(2)(-) formation, NOX-1 expression and Rac(1) activity were assessed. The possible interaction between H(2)S and NO was also studied by using an NO synthase inhibitor, L-NAME, and an NO donor, DETA-NONOate. The role of K(ATP) channels was studied by using glibenclamide. NaHS inhibited O(2)(-) formation following incubation of 1 h (IC(50), 30 nM) and 16 h (IC(50), 20 nM), blocked NOX-1 expression and inhibited Rac(1) activity. These inhibitory effects of NaHS were mediated by the cAMP-protein-kinase-A axis. Exogenous H(2)S prevents NOX-driven intravascular oxidative stress through an a priori inhibition of Rac(1) and downregulation of NOX-1 protein expression, an effect mediated by activation of the adenylylcyclase-cAMP-protein-kinase-G system by H(2)S.
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PMID:Exogenous hydrogen sulfide inhibits superoxide formation, NOX-1 expression and Rac1 activity in human vascular smooth muscle cells. 1846 17

A wide variety of reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical and hydrogen peroxide, and reactive nitrogen species such as nitric oxide (NO) and peroxynitrite are known to be involved in pathophysiology of bronchial asthma. We have investigated, in this study, the status of NADPH oxidase (NOX), a major source of superoxide anion production, in peripheral blood lymphocytes (PBL) from asthmatic patients in relation to salbutamol treatment. PBL isolated from patients with bronchial asthma were found to have a significantly increased activity of NOX. Plasma levels of malondialdehyde (MDA), an index of lipid peroxidation, and NO were also markedly elevated in asthmatic patients compared to control samples. A significantly decreased catalase activity observed in PBL from our patients underscored the severity of oxidative stress during asthma. Treatment of PBL with salbutamol (10 microg ml(-1)), prevented the attenuation of catalase activity but significantly increased the levels of NO and NOX activity. Levels of NOX-1 mRNA were significantly (p < 0.001) increased in PBL following treatment with NO donor (500 microM), S-nitroso-N-acetyl penicillamine (SNAP). Western blot analysis revealed that gp91phox protein was also significantly (twofold-threefold) increased following treatment with SNAP. The observed transcriptional regulation of NOX-1 and gp91phox by NO was observed to result in an increased NOX activity as well. This study concludes that salbutamol treatment enhances superoxide anion production in asthma patients through NO-mediated mechanisms, however it exerts beneficial antioxidant effects through activation of catalase and attenuation of lipid peroxidation.
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PMID:Nitric oxide-mediated activation of NADPH oxidase by salbutamol during acute asthma in children. 1850 84

We have proposed that reactive oxygen species (ROS) play essential roles in cell differentiation. Enzymes belonging to the NADPH oxidase (NOX) family produce superoxide in a regulated manner. We have identified three distinct NOX subfamilies in the fungal kingdom and have shown that NoxA is required for sexual cell differentiation in Aspergillus nidulans. Here we show that Neurospora crassa NOX-1 elimination results in complete female sterility, decreased asexual development, and reduction of hyphal growth. The lack of NOX-2 did not affect any of these processes but led instead to the production of sexual spores that failed to germinate, even in the presence of exogenous oxidants. The elimination of NOR-1, an ortholog of the mammalian Nox2 regulatory subunit gp67(phox), also caused female sterility, the production of unviable sexual spores, and a decrease in asexual development and hyphal growth. These results indicate that NOR-1 is required for NOX-1 and NOX-2 functions at different developmental stages and establish a link between NOX-generated ROS and the regulation of growth. Indeed, NOX-1 was required for the increased asexual sporulation previously observed in mutants without catalase CAT-3. We also analyzed the function of the penta-EF calcium-binding domain protein PEF-1 in N. crassa. Deletion of pef-1 resulted in increased conidiation but, in contrast to what occurs in Dictyostelium discoideum, the mutation of this peflin did not suppress the phenotypes caused by the lack of NOX-1. Our results support the role of ROS as critical cell differentiation signals and highlight a novel role for ROS in regulation of fungal growth.
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PMID:NADPH oxidases NOX-1 and NOX-2 require the regulatory subunit NOR-1 to control cell differentiation and growth in Neurospora crassa. 1856 88

Oxidative stress is the common downstream effect of a variety of environmental neurotoxins that are strongly implicated in the pathogenesis of Parkinson's disease. We demonstrate here that the activation of NADPH oxidase 1 (Nox1), a specialized superoxide-generating enzyme complex, plays a key role in the oxidative stress and subsequent dopaminergic cell death elicited by paraquat. Paraquat increased the expression of Nox1 in a concentration-dependent manner in rat dopaminergic N27 cells. Rac1, a key component necessary for Nox1-mediated superoxide generation, also was activated by paraquat. Paraquat-induced reactive oxygen species generation and dopaminergic cell death were significantly reduced after pretreatment with apocynin, a putative NADPH oxidase inhibitor, and Nox1 knockdown with siRNA. Male C57BL/6 mice received intraperitoneal (IP) injections of paraquat (10 mg/kg) once every 3 days and showed increased Nox1 levels in the substantia nigra as well as a 35% reduction in tyrosine hydroxylase-positive dopaminergic neurons 5 days after the last injection. Preadministration of apocynin (200 mg/kg, IP) led to a significant decrease in dopaminergic neuronal loss. Our results suggest that Nox1-generated superoxide is implicated in the oxidative stress elicited by paraquat in DA cells, and it can serve as a novel target for pharmacologic intervention.
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PMID:The role of NADPH oxidase 1-derived reactive oxygen species in paraquat-mediated dopaminergic cell death. 1945 58

Rac1 and Rac2, which belong to the Rho subfamily of Ras-related GTPases, play an essential role in activation of gp91phox/Nox2 (cytochrome b-245, beta polypeptide; also known as Cybb), the catalytic core of the superoxide-producing NADPH oxidase in phagocytes. Rac1 also contributes to activation of the non-phagocytic oxidases Nox1 (NADPH oxidase 1) and Nox3 (NADPH oxidase 3), each related closely to gp91phox/Nox2. It has remained controversial whether the insert region of Rac (amino acids 123-135), unique to the Rho subfamily proteins, is involved in gp91phox/Nox2 activation. In the present study we show that removal of the insert region from Rac1 neither affects activation of gp91phox/Nox2, which is reconstituted under cell-free and whole-cell conditions, nor blocks its localization to phagosomes during ingestion of IgG-coated beads by macrophage-like RAW264.7 cells. The insert region of Rac2 is also dispensable for gp91phox/Nox2 activation at the cellular level. Although Rac2, as well as Rac1, is capable of enhancing superoxide production by Nox1 and Nox3, the enhancements by the two GTPases are both independent of the insert region. We also demonstrate that Rac3, a third member of the Rac family in mammals, has an ability to activate the three oxidases and that the activation does not require the insert region. Thus the insert region of the Rac GTPases does not participate in regulation of the Nox family NADPH oxidases.
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PMID:The insert region of the Rac GTPases is dispensable for activation of superoxide-producing NADPH oxidases. 1953 24

Cyclin kinase inhibitor p21 is one of the most potent inhibitors of aortic smooth muscle cell proliferation, a key mediator of atherosclerosis. This study tests if p2l deficiency will result in severe atherosclerosis in a mouse model. p21-/- and strain matched wild type mice were fed with high fat diet for 21 weeks. Analysis for biochemical parameters (cholesterol, triglycerides) in serum and mRNA expression of CD36, HO-1, TGF-beta, IFN-gamma, TNF-alpha, PPAR-gamma and NADPH oxidase components (p22phox, NOX-1 and Rac-1) was performed in aortic tissues by Real Time PCR. p21-/- mice gained significantly (p < 0.01) more weight than wild type mice, triglycerides (p < 0.05) and cholesterol levels (p < 0.01) were more pronounced in the sera of p21-/- compared to wild type mice fed with high fat diet. High fat diet resulted in significantly decreased TGF-beta (p < 0.02), HO-l (p < 0.02) and increased CD36 (p < 0.03) mRNA expression in aortic tissues of p21-/- mice compared to animal fed with regular diet. IFN-gamma mRNA expression (235 +/- 11 folds) increased significantly in high fat diet fed p21-/- mice and a multifold modulation of PPAR-gamma(136 +/- 7), p22phox, NOX-1 and Rac-1 (15-35-folds) mRNA in aortic tissues from p21-/- mice compared to the wild type mice. Severity of atherosclerotic lesions was significantly higher in p21-/- compared to wild type mice. The results demonstrate that the deficiency of p21 leads to altered expression of pro-atherogenic genes, and severe atherosclerosis in mice fed with high fat diet. This opens the possibility of p21 protein as a therapeutic tool to control progression of atherosclerosis.
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PMID:Enhanced susceptibility of cyclin kinase inhibitor p21 knockout mice to high fat diet induced atherosclerosis. 1960 72


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