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)

We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles from diabetic rats in vitro with alpha-lipoic acid, dihydrolipoic acid, tempol or arginine restores acetylcholine-mediated vascular relaxation to near the reactivity observed in vessels from control rats. Suggesting that increased oxidative stress and reduction in nitric oxide availability is partially responsible for the impairment in endothelium-dependent vasodilation observed in epineurial arterioles from diabetic rats. In contrast, pretreating epineurial arterioles from diabetic rats with aminoguanidine or allopurinol had no effect. Studies designed to investigate the source of superoxide formation provided results suggesting that complex I of the mitochondrial electron transport chain and NAD(P)H oxidase are responsible for the increase in superoxide formation observed with epineurial arterioles from the sciatic nerve. Pretreating epineurial arterioles from diabetic rats with the protein kinase C inhibitor bisindolymaleimide I (GF 109203X) improved acetylcholine-mediated vascular relaxation but did not prevent the increase in superoxide formation suggesting that activation of protein kinase C by oxidative stress is downstream of superoxide formation. These studies imply that increased superoxide formation via the mitochondrial electron transport chain and perhaps NAD(P)H oxidase is partially responsible for reduced vascular reactivity observed in epineurial arterioles of the sciatic nerve from diabetic rats.
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PMID:Preventing superoxide formation in epineurial arterioles of the sciatic nerve from diabetic rats restores endothelium-dependent vasodilation. 1265 15

Exposure to atherogenic levels of low-density lipoprotein (LDL) causes elevated reactive oxygen species (ROS) production by human endothelial cells (ECs). NADPH oxidase is thought to be the main source of ROS generated by LDL-activated ECs. The mechanism by which this lipoprotein activates endothelial NADPH oxidase is incompletely understood. To gain further insight into the signaling pathway, the authors have examined the effects of inhibitors to various signal transducing enzymes, including the G(i)-protein coupled receptor (pertussis toxin), Src tyrosine kinase (PP1), phospholipase C-gamma (U73122), phosphatidylinositol 3-kinase (LY294002), p42/p44 mitogen-activated protein kinase (MAPK) kinase (PD98059), p38 MAPK (SB203580), protein kinase C (Ro 318220, GF 109203X, Go 6976), and cytosolic phospholipase A(2) (AACOCF3), on the ROS-producing capacity ECs activated by LDL. Exposure of cultured ECs to LDL (0.45 mg protein/mL) stimulated ROS formation, as measured using a 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate assay. This effect was partially inhibited by Ro 318220, GF 109203X, U73122, and SB203580, and blocked or nearly completely inhibited by PP1, pertussis toxin, LY294002, PD98059, and AACOCF3. Only a partial, minor inhibition occurred with the protein kinase C inhibitor, Go 6976. These results are most consistent with LDL activating endothelial NADPH oxidase, predominantly through a signaling pathway that leads to cytosolic phospholipase A(2) activation.
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PMID:Endothelial NADPH oxidase: mechanism of activation by low-density lipoprotein. 1474 44

Cyclic AMP affects microvascular smooth muscle contraction and growth. Therefore, it is important to elucidate mechanisms regulating cyclic AMP production in microvascular smooth muscle. In this study, we determined whether several signal transduction pathways regulate receptor-induced cyclic AMP in isolated preglomerular microvessels and microvascular smooth muscle cells. Preglomerular microvessels were incubated with isoproterenol (beta-adrenoceptor agonist) and with and without U73122 (phospholipase C inhibitor), GF109203X (protein kinase C inhibitor), 1-butanol (phospholipase D inhibitor), CGP77675 (c-src inhibitor), HA1077 (Rho kinase inhibitor), Y27632 (Rho kinase inhibitor), LY294002 (phosphatidylinositol-3-kinase inhibitor), dipenyleneiodonium (NADPH oxidase inhibitor), or Tempol (superoxide dismutase mimetic). Cultured preglomerular microvascular smooth muscle cells were incubated with isoproterenol or forskolin (direct activator of adenylyl cyclase) and with or without U73122, C(2)-ceramide (phospholipase D inhibitor), or PP1 [src family inhibitor, 1-(1,1-dimethylethyl)-1-(4-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine]. All studies were conducted with 3-isobutyl-1-methylxanthine (broad-spectrum phosphodiesterase inhibitor) to eliminate changes in cyclic AMP degradation. In microvessels isoproterenol-induced cyclic AMP was not affected by Y27632, HA1007, LY294002, dipenylene-iodonium, or Tempol; was increased by U73122 and GF109203X; and was decreased by 1-butanol and CGP77675. In cells, U73122 increased and C(2)-ceramide and PP1 decreased isoproterenol-induced cyclic AMP. Forskolin-induced cyclic AMP was not altered. These results indicate that receptor-mediated activation of adenylyl cyclase is 1) not modulated by Rho kinase, phosphatidylinositol-3-kinase, NADPH oxidase, or superoxide; 2) is attenuated by phospholipase C and protein kinase C; and 3) is augmented by phospholipase D and src. Phospholipase C, phospholipase D, and src modulate receptor-induced cyclic AMP by affecting beta-adrenoreceptor/G protein/adenylyl cyclase coupling rather than by directly affecting adenylyl cyclase activity.
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PMID:Modulation of cyclic AMP production by signal transduction pathways in preglomerular microvessels and microvascular smooth muscle cells. 1508 74

Polybrominated diphenyl ethers (PBDEs) are widely used brominated flame retardants (BFRs), which have become ubiquitous in the environment. This study investigates the effects of the pentabrominated diphenyl ether mixture, DE-71, on human neutrophil granulocytes in vitro. DE-71 enhanced production of reactive oxygen species (ROS) in a concentration-dependent manner measured as lucigenin-amplified chemiluminescence. Octabrominated diphenyl ether (OBDE), decabrominated diphenyl ether (DBDE), and the non-brominated diphenyl ether did not induce ROS formation at the concentrations tested. DPI (4 microM), an inhibitor of the NADPH oxidase completely inhibited DE-71 induced ROS formation, highlighting a role for NADPH oxidase activation. The protein kinase C inhibitor BIM (0.25 microM) and the selective chelator of intracellular calcium, BAPTA-AM (5 microM), also inhibited NADPH oxidase activation, indicating a calcium-dependent activation of PKC. ROS formation was also inhibited by the tyrosine kinase inhibitor tyrphostin (1 microM), the phospholipase C inhibitor ET-18-OCH3 (5 microM), and the phosphatidylinositol-3 kinase inhibitor LY294002 (25 microM). Alterations in intracellular calcium were measured using fura-2/AM, and a significant increase was measured after exposure to DE-71 both with and without extracellular calcium. The tetra brominated compound BDE-47 also enhanced ROS formation in a concentration dependent manner. The combination of DE-71 with the bacteria-derived N-formyl peptide fMLP and PCB153 induced an additive effect in the lucigenin assay. We suggest that tyrosine kinase mediated activation of PI3K could result in enhanced activation of calcium-dependent PKC by enhanced PLC activity, followed by intracellular calcium release leading to ROS formation in neutrophil granulocytes.
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PMID:A commercial mixture of the brominated flame retardant pentabrominated diphenyl ether (DE-71) induces respiratory burst in human neutrophil granulocytes in vitro. 1595 60

Oxidant stress plays a crucial role in the triggering of cardioprotection involving ischemic preconditioning (IPC). We have used biotin-tagged cysteine to probe for redox-modified proteins in IPC protocols. Cysteine was biotinylated and introduced into isolated rat hearts. S-Thiolated proteins were detected and quantified using nonreducing western blots probed with streptavidin-horseradish peroxidase. Controls (15 min of aerobic perfusion plus 5 min of 0.5 mM biotin-cysteine plus 5 min of aerobic perfusion) showed low-level protein S-thiolation. Hearts preconditioned with 5 min of ischemia and reperfused for 5 min with biotin-cysteine plus 5 min of aerobic perfusion showed increased thiolation (160%) that was fully blocked by the antioxidant mercaptopropionylglycine, which is also known to block IPC. "Preconditioning" agonists (phorbol 12-myristate 13-acetate or phenylephrine) or oxidants (hydrogen peroxide or diamide) administered during aerobic preparations to biotin-cysteine-loaded hearts induced efficient protein S-thiolation. Preconditioning agonist-induced S-thiolation was significantly attenuated by diphenyleneiodonium (a flavoprotein inhibitor) or by the protein kinase C inhibitor bisindolylmaleimide I. Additional studies testing the role of a Nox2-containing NAD(P)H oxidase as the source of the oxidant stress essential to the triggering IPC showed that protein S-thiolation was the same in wild-type and Nox2 knockout mice.
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PMID:Ischemic preconditioning: a potential role for protein S-thiolation? 1599 43

Oxidative stress plays a critical role in the pathogenesis of atherosclerosis in patients with metabolic syndrome. This study aimed to investigate whether a relationship exists between phagocytic NADPH oxidase activity and oxidative stress and atherosclerosis in metabolic syndrome patients. The study was performed in 56 metabolic syndrome patients (metabolic syndrome group), 99 patients with one or two cardiovascular risk factors (cardiovascular risk factor group), and 28 healthy subjects (control group). NADPH oxidase expression and activity was augmented (P < 0.05) in metabolic syndrome compared with cardiovascular risk factor and control groups. Insulin was enhanced (P < 0.05) in metabolic syndrome patients compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. Insulin stimulated NADPH oxidase activity; this effect was abolished by a specific protein kinase C inhibitor. Oxidized LDL and nitrotyrosine levels and carotid intima-media thickness were increased (P < 0.05) in the metabolic syndrome group compared with cardiovascular risk factor and control groups and correlated with NADPH oxidase activity in the overall population. These findings suggest that phagocytic NADPH oxidase overactivity is involved in oxidative stress and atherosclerosis in metabolic syndrome patients. Our findings also suggest that hyperinsulinemia may contribute to oxidative stress in metabolic syndrome patients through activation of NADPH oxidase.
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PMID:Phagocytic NADPH oxidase overactivity underlies oxidative stress in metabolic syndrome. 1638 Apr 95

Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO.) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO. was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography -based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H2O2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), N(G)-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22(phox) subunit of NADPH oxidase with small interfering RNA also inhibited Ang II-mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II-induced decrease in endothelial NO. and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO. and generation, which in turn has ramifications for development of endothelial dysfunction.
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PMID:Molecular mechanisms of angiotensin II-mediated mitochondrial dysfunction: linking mitochondrial oxidative damage and vascular endothelial dysfunction. 2442 12

Activation of the endothelium plays an important role in the innate immune response. This process is associated with an increase in the production of superoxide (O2-) by nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) oxidase. Our objective was to determine if O2- from NADPH oxidase contributes to activation of human umbilical vein endothelial cells by LPS as it does for TNF-alpha. We used the adhesion molecule intracellular adhesion molecule 1 and cytokine IL-8 as indicators of human umbilical vein endothelial cell activation and measured O2- production with chemiluminescence. LPS increased baseline and NADPH-stimulated O2- production. The increase was reduced by tiron, a protein kinase C inhibitor (bisindolylmaleimide I hydrochloride), the flavin inhibitor (diphenylene iodonium), and by a short interfering RNA against the p22phox component of NADPH oxidase. Inhibition of NADPH oxidase with the short interfering RNA reduced the induction by LPS of intracellular adhesion molecule 1 mRNA, protein, and IL-8 release (by enzyme-linked immunosorbent assay). The production of O2- by NADPH oxidase contributes to intracellular signaling by LPS in endothelial cells as it does for TNF-alpha and helps turn on the innate immune response in these cells.
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PMID:Nicotinamide adenine dinucleotide phosphate (reduced form) oxidase is important for LPS-induced endothelial cell activation. 1841 30

Sulfonylureas are considered to cause beta-cell apoptosis. However, it is unclear how this occurs and whether there is a difference in such effects among various sulfonylureas. Here, we examined the effects of various sulfonylureas and a short-acting insulin secretagogue, nateglinide, on oxidative stress and apoptosis using the beta-cell line MIN6. After cultured MIN6 cells were exposed to various concentrations of sulfonylureas (glibenclamide, glimepiride, and gliclazide) or nateglinide, intracellular production of reactive oxygen species (ROS) was evaluated by staining with 2',7'-dichlorofluorescein diacetate. The effect of these agents on apoptosis was also evaluated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling technique. Exposure of beta-cells to glibenclamide, glimepiride, and nateglinide significantly increased intracellular ROS production in a concentration-dependent manner (0.1-10 micromol/L). These effects were completely blocked by nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase inhibitors (diphenylene iodonium or apocynin) or a protein kinase C inhibitor (calphostin C). After exposure to these agents for 48 hours, the numbers of apoptotic cells were also significantly increased. These effects were significantly blocked by apocynin and antioxidant N-acetyl-L-cysteine. In contrast, exposure to any concentrations of gliclazide did not affect either intracellular ROS production or the numbers of apoptotic cells. Sulfonylureas (glibenclamide and glimepiride, but not gliclazide) and nateglinide stimulated ROS production via protein kinase C-dependent activation of NAD(P)H oxidase and consequently caused beta-cell apoptosis in vitro. Because of the lack of such adverse effects, gliclazide may have a benefit in the preservation of functional beta-cell mass.
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PMID:Differential effect of sulfonylureas on production of reactive oxygen species and apoptosis in cultured pancreatic beta-cell line, MIN6. 1864 Mar 79

Skeletal muscle is one of the main physiological targets of insulin, a hormone that triggers a complex signaling cascade and that enhances the production of reactive oxygen species (ROS) in different cell types. ROS, currently considered second messengers, produce redox modifications in proteins such as ion channels that induce changes in their functional properties. In myotubes, insulin also enhances calcium release from intracellular stores. In this work, we studied in myotubes whether insulin stimulated ROS production and investigated the mechanisms underlying the insulin-dependent calcium increase: in particular, whether the late phase of the Ca2+ increase induced by insulin required ROS. We found that insulin stimulated ROS production, as detected with the probe 2',7'-dichlorofluorescein diacetate (CM-H2DCFDA). We used the translocation of p47phox from the cytoplasm to the plasma membrane as a marker of the activation of NADPH oxidase. Insulin-stimulated ROS generation was suppressed by the NADPH oxidase inhibitor apocynin and by small interfering RNA against p47phox, a regulatory NADPH oxidase subunit. Additionally, both protein kinase C and phosphatidylinositol 3-kinase are presumably involved in insulin-induced ROS generation because bisindolylmaleimide, a nonspecific protein kinase C inhibitor, and LY290042, an inhibitor of phosphatidylinositol 3-kinase, inhibited this increase. Bisindolylmaleimide, LY290042, apocynin, small interfering RNA against p47phox, and two drugs that interfere with inositol 1,4,5-trisphosphate-mediated Ca2+ release, xestospongin C and U73122, inhibited the intracellular Ca2+ increase produced by insulin. These combined results strongly suggest that insulin induces ROS generation trough NADPH activation and that this ROS increase is required for the intracellular Ca2+ rise mediated by inositol 1,4,5-trisphosphate receptors.
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PMID:NADPH oxidase and hydrogen peroxide mediate insulin-induced calcium increase in skeletal muscle cells. 1902 99


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