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)

Reactive oxygen species (ROS) play a central role in the pathogenesis of many cardiovascular diseases, such as atherosclerosis and hypertension. Endothelial NADPH oxidase is the major source of intracellular ROS. The present study investigated the role of endothelial NADPH oxidase-derived ROS in angiopoietin-1 (Ang-1)-induced angiogenesis. Exposure of porcine coronary artery endothelial cells (PCAECs) to Ang-1 (250 ng/ml) for periods up to 30 min led to a transient and dose-dependent increase in intracellular ROS. Thirty minutes of pretreatment with the NADPH oxidase inhibitors diphenylene iodinium (DPI, 10 microM) and apocynin (200 microM) suppressed Ang-1-stimulated ROS. Pretreatment with either DPI or apocynin also significantly attenuated Ang-1-induced Akt and p44/42 MAPK phosphorylation. In addition, inhibition of NADPH oxidase significantly suppressed Ang-1-induced endothelial cell migration and sprouting from endothelial spheroids. Using mouse heart microvascular endothelial cells from wild-type (WT) mice and mice deficient in the p47(phox) component of NADPH oxidase (p47(phox-/-)), we found that although Ang-1 stimulated intracellular ROS, Akt and p42/44 MAPK phosphorylation, and cell migration in WT cells, the responses were strikingly suppressed in cells from the p47(phox-/-) mice. Furthermore, exposure of aortic rings from p47(phox-/-) mice to Ang-1 demonstrated fewer vessel sprouts than WT mice. Inhibition of the Tie-2 receptor inhibited Ang-1-induced endothelial migration and vessel sprouting. Together, our data strongly suggest that endothelial NADPH oxidase-derived ROS play a critical role in Ang-1-induced angiogenesis.
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PMID:Angiopoietin-1-induced angiogenesis is modulated by endothelial NADPH oxidase. 1667 92

Electrophysiological events are of central importance during the phagocyte respiratory burst, because NADPH oxidase is electrogenic and voltage sensitive. We investigated the recent suggestion that large-conductance, calcium-activated K(+) (BK) channels, rather than proton channels, play an essential role in innate immunity (Ahluwalia, J., A. Tinker, L.H. Clapp, M.R. Duchen, A.Y. Abramov, S. Page, M. Nobles, and A.W. Segal. 2004. Nature. 427:853-858). In PMA-stimulated human neutrophils or eosinophils, we did not detect BK currents, and neither of the BK channel inhibitors iberiotoxin or paxilline nor DPI inhibited any component of outward current. BK inhibitors did not inhibit the killing of bacteria, nor did they affect NADPH oxidase-dependent degradation of bacterial phospholipids by extracellular gIIA-PLA(2) or the production of superoxide anion (O(2*)(-)). Moreover, an antibody against the BK channel did not detect immunoreactive protein in human neutrophils. A required role for voltage-gated proton channels is demonstrated by Zn(2+) inhibition of NADPH oxidase activity assessed by H(2)O(2) production, thus validating previous studies showing that Zn(2+) inhibited O(2*)(-) production when assessed by cytochrome c reduction. In conclusion, BK channels were not detected in human neutrophils or eosinophils, and BK inhibitors did not impair antimicrobial activity. In contrast, we present additional evidence that voltage-gated proton channels serve the essential role of charge compensation during the respiratory burst.
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PMID:The antibacterial activity of human neutrophils and eosinophils requires proton channels but not BK channels. 1670 53

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Tumor necrosis factor-alpha (TNF-alpha) enhances NAD (P) H oxidase-dependent reactive oxygen species (ROS) formation and ROS induce MMP-2. In the present study, the effects of a potent water-soluble antioxidant, salvianolic acid B (SalB), derived from a Chinese herb, Salvia miltiorrhiza, on the expression of MMP-2 by TNF-alpha-treated human aortic smooth muscle cells (HASMCs) were investigated. In this study, salvianolic acid B scavenged H2O2 in a dose-dependent manner in test tube. We found that SalB, as well as NADPH oxidase inhibitors, DPI or apocynin, and antioxidant NAC, inhibited TNF-alpha-induced MMP-2 mRNA, protein expression, and gelatinolytic activity in HASMCs in a concentration-dependent manner. We also observed a dose-dependent decrease in ROS production and NADPH oxidase activity induced by TNF-alpha in the presence of SalB. SalB also significantly inhibited angiotensin II or H2O2-induced MMP-2 mRNA and protein expression and gelatinolytic activity in HASMCs. Our data point out that the importance of NADPH oxidase-dependent ROS generation in the control of SalB inhibition of TNF-alpha-induced MMP-2 expression and activity.
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PMID:Salvianolic acid B from Salvia miltiorrhiza inhibits tumor necrosis factor-alpha (TNF-alpha)-induced MMP-2 upregulation in human aortic smooth muscle cells via suppression of NAD(P)H oxidase-derived reactive oxygen species. 1671 3

Matrix metalloproteinase 9 (MMP-9) is a crucial proteinase, utilized by both eosinophils and neutrophils, that mediates transmigration through extracellular basement membranes. We have found that neutralization of MMP-9 by a monoclonal antibody or a chemical inhibitor blocked C5a dependent chemotaxis of these granulocytes in vitro. The levels of MMP-9 secreted by the action of C5a from eosinophils were about 50-fold lower than those from neutrophils, consistent with results from confocal microscopy, where the density of MMP-9 containing granules was fewer within eosinophils than in neutrophils. Zymography indicated gelatin degrading activity of the molecular size of pro MMP-9 in supernatants from eosinophils and neutrophils stimulated by C5a, with no evidence of proteolytic activation. Instead MMP-9 activation appeared oxidative, since inhibition of NADPH oxidase and nitric oxide synthase by DPI or L-NIL abrogated C5a-mediated chemotaxis through basement membranes. In keeping with this mode of activation, C5a, known as an agent of superoxide generation, was also found to induce secretion of nitric oxide from human eosinophils and rat granulocytes and monocytes. In conclusion C5a is an important mediator that brings about secretion and oxidative activation of MMP-9, a requisite protease for transmigration, from both eosinophils and neutrophils.
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PMID:C5a mediates secretion and activation of matrix metalloproteinase 9 from human eosinophils and neutrophils. 1671 14

The dopaminergic system appears early in mammalian brain development, and a neurodevelopmental role for dopamine (DA) has been suggested. In the present study, we found that DA markedly promoted the survival of embryonic striatal cells in cultures. The failure of DA receptor antagonists to block this survival-promoting effect and the capability of S-apomorphine, which is devoid of DA receptor agonist activity but possesses antioxidative activity as R-apomorphine and DA, to completely mimic this effect suggested that DA receptor activation was not required in the survival-promoting effect elicited by DA, and its antioxidative activity might be involved. Moreover, it was found that mRNA of NADPH oxidase was expressed in the embryonic striatum. Furthermore, DPI or apocynin, NADPH oxidase inhibitors, promoted the survival of embryonic striatal cells. Addition of either DA or DPI into striatal cell cultures decreased the superoxide level. These results indicate that the mechanisms underlying the neuroprotective effects of DA were likely associated with its antioxidative activity. NADPH oxidase might contribute, at least in part, to ROS generation.
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PMID:Dopamine promotes the survival of embryonic striatal cells: involvement of superoxide and endogenous NADPH oxidase. 1675 54

Nuclear factor kappa B (NF-kappaB) is a redox-associated transcription factor that is involved in the activation of survival pathways. We have previously shown that deoxycholate (DOC) activates NF-kappaB in hepatocytes and colon epithelial cells and that persistent exposure of HCT-116 cells to increasing concentrations of DOC results in the constitutive activation of NF-kappaB, which is associated with the development of apoptosis resistance. The mechanisms by which DOC activates NF-kappaB in colon epithelial cells, and whether natural antioxidants can reduce DOC-induced NF-kappaB activation, however, are not known. Also, it is not known if DOC can generate reactive oxygen species within mitochondria as a possible pathway of stress-related NF-kappaB activation. Since we have previously shown that DOC activates the NF-kappaB stress-response pathway in HCT-116 cells, we used this cell line to further explore the mechanisms of NF-kappaB activation. We found that DOC induces mitochondrial oxidative stress and activates NF-kappaB in HCT-116 cells through multiple mechanisms involving NAD(P)H oxidase, Na+/K+-ATPase, cytochrome P450, Ca++ and the terminal mitochondrial respiratory complex IV. DOC-induced NF-kappaB activation was significantly (P < 0.05) inhibited by pre-treatment of cells with CAPE, EGCG, TMS, DPI, NaN3, EGTA, Ouabain and RuR. The NF-kappaB-activating pathways, induced by the dietary-related endogenous detergent DOC, provide mechanisms for promotion of colon cancer and identify possible new targets for chemoprevention.
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PMID:Deoxycholate induces mitochondrial oxidative stress and activates NF-kappaB through multiple mechanisms in HCT-116 colon epithelial cells. 1688 64

NF-kappaB signaling pathway has been known to play a major role in the pathological process of atherogenesis. Unlike high shear stress, in which the NF-kappaB activity is transient, our earlier studies have demonstrated a persistent activation of NF-kappaB in response to low shear stress in human aortic endothelial cells. These findings partially explained why low shear regions that exist at bifurcations of arteries are prone to atherosclerosis, unlike the relatively atheroprotective high shear regions. In the present study, we further investigated 1) the role of NF-kappaB signaling kinases (IKKalpha and beta) that may be responsible for the sustained activation of NF-kappaB in low shear stress and 2) the regulation of these kinases by reactive oxygen species (ROS). Our results demonstrate that not only is a significant proportion of low shear-induced-kinase activity is contributed by IKKbeta, but it is also persistently induced for a prolonged time frame. The IKK activity (both alpha and beta) is blocked by apocynin (400 microM), a specific NADPH oxidase inhibitor, and diphenyleneiodonium chloride (DPI; 10 microM), an inhibitor of flavin-containing oxidases like NADPH oxidases. Determination of ROS also demonstrated an increased generation in low shear stress that could be blocked by DPI. These results suggest that the source of ROS generation in endothelial cells in response to low shear stress is NADPH oxidase. The DPI-inhibitable component of ROS is the primary regulator of specific upstream kinases that determine the persistent NF-kappaB activation selectively in low shear-induced endothelial cells.
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PMID:Low shear stress preferentially enhances IKK activity through selective sources of ROS for persistent activation of NF-kappaB in endothelial cells. 1691 32

M-CSF induces PI 3-kinase activation, resulting in reactive oxygen species (ROS) production. Previously, we reported that ROS mediate macrophage colony-stimulating factor (M-CSF)-induced extracellular regulated kinase (Erk) activation and monocyte survival. In this work, we hypothesized that M-CSF-stimulated ROS products modulated Akt1 and p38 activation. Furthermore, we sought to clarify the source of these ROS and the role of ROS and Akt in monocyte/macrophage survival. Macrophages from p47(phox-/-) mice, lacking a key component of the NADPH oxidase complex required for ROS generation, had reduced cell survival and Akt1 and p38 mitogen-activated protein kinase (MAPK) phosphorylation compared with wild-type macrophages in response to M-CSF stimulation, but had no difference in M-CSF-stimulated Erk. To understand how ROS affected monocyte survival and signaling, we observed that NAC and DPI decreased cell survival and Akt1 and p38 MAPK phosphorylation. Using bone marrow-derived macrophages from mice expressing constitutively activated Akt1 (Myr-Akt1) or transfecting Myr-Akt1 constructs into human peripheral monocytes, we concluded that Akt is a positive regulator of monocyte survival. Moreover, the p38 MAPK inhibitor, SB203580, inhibited p38 activity and M-CSF-induced monocyte survival. These findings demonstrate that ROS generated from the NADPH oxidase complex contribute to monocyte/macrophage survival induced by M-CSF via regulation of Akt and p38 MAPK.
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PMID:The role of the NADPH oxidase complex, p38 MAPK, and Akt in regulating human monocyte/macrophage survival. 1693 6

We reported previously that salinity-induced elongation constraints in the expansion zone of maize leaves are associated with reduced reactive oxygen species (ROS) production and could be alleviated by the addition of ROS. The NaCl effect was salt-specific and not osmotic. This paper explores the causes for such reduction. The decrease in ROS levels under salinity was not accompanied by increases in soluble apoplastic antioxidant activities such as superoxide dismutase, peroxidases and ascorbate. In experimental systems devoid of cell walls (protoplasts and membrane fractions) superoxide anion (O(2)(-)) production was inhibited by 50 and 100 mM NaCl, 50 microM DPI, 10 mM EGTA, and 5mM verapamil, a Ca(2+) channel inhibitor. Inhibitory effects of NaCl and reduced Ca(2+) supply were also observed in in gel assessment of O(2)(-) -generating activity. The main activity band excised from the ND-PAGE was recognized by an antibody against the C-terminal portion of the tomato gp91(phox) homolog. These results indicate the *O(2)(-) -generating activity negatively affected by NaCl was compatible with that of plasma membrane NADPH oxidase.
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PMID:Salinity-induced decrease in NADPH oxidase activity in the maize leaf blade elongation zone. 1707 8

The presence of 2 mM bicarbonate in the incubation medium induced stomatal closure in abaxial epidermis of Arabidopsis. Exposure to 2 mM bicarbonate elevated the levels of H(2)O(2) in guard cells within 5 min, as indicated by the fluorescent probe, dichlorofluorescein diacetate (H(2)DCF-DA). Bicarbonate-induced stomatal closure as well as H(2)O(2) production were restricted by exogenous catalase or diphenylene iodonium (DPI, an inhibitor of NAD(P)H oxidase). The reduced sensitivity of stomata to bicarbonate and H(2)O(2) production in homozygous atrbohD/F double mutant of Arabidopsis confirmed that NADP(H) oxidase is involved during bicarbonate induced ROS production in guard cells. The production of H(2)O(2) was quicker and greater with ABA than that with bicarbonate. Such pattern of H(2)O(2) production may be one of the reasons for ABA being more effective than bicarbonate, in promoting stomatal closure. Our results demonstrate that H(2)O(2) is an essential secondary messenger during bicarbonate induced stomatal closure in Arabidopsis.
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PMID:Hydrogen peroxide production is an early event during bicarbonate induced stomatal closure in abaxial epidermis of Arabidopsis. 1716 Mar 88


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