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 tested the hypothesis that short-term treatment of mice with Type 2 diabetes mellitus (DM) with rosiglitazone (ROSI), an agonist of peroxisome proliferator-activated receptor-gamma, ameliorates the impaired coronary arteriolar dilation by reducing oxidative stress via a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia. Control and Type 2 DM (db/db) mice were treated with ROSI (3 mg x kg(-1) x day(-1)) for 7 days, which did not significantly affect their serum concentration of glucose and insulin. Compared with controls, in db/db mice serum levels of 8-isoprostane and dihydroethydine-detectable superoxide production in carotid arteries were significantly elevated and were reduced by ROSI treatment. In coronary arterioles (diameter, approximately 80 microm) isolated from db/db mice, the reduced dilations to ACh, the nitric oxide (NO) donor NONOate, and increases in flow were significantly augmented either by in vitro administration of apocynin, an inhibitor of NAD(P)H-oxidase, or by in vivo ROSI treatment, responses that were then significantly reduced by the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester. In aortas of db/db mice, activity of SOD and catalase was reduced, whereas NAD(P)H oxidase activity was enhanced. ROSI treatment enhanced catalase and reduced NAD(P)H oxidase activity but did not affect the activity of SOD. These findings suggest that ROSI treatment enhances NO mediation of coronary arteriolar dilations due to the reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. Thus, in addition to the previously revealed beneficial metabolic effects, the antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.
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PMID:PPARgamma activation, by reducing oxidative stress, increases NO bioavailability in coronary arterioles of mice with Type 2 diabetes. 1455 Oct 45

A series of isomeric methoxyindazoles has been evaluated as inhibitors of purified recombinant neuronal, inducible, and endothelial nitric oxide synthases (NOS). 7-Methoxyindazole (7-MI) was the most active compound of this series and displayed selectivity toward the constitutive neuronal (NOS I) and endothelial (NOS III) NOS isoforms, the inducible NOS II being almost insensitive to this inhibitor. 6-, 5-, and 4-Methoxyindazoles were almost inactive against all three NOS isoforms. Inhibition of NO and citrulline formation catalyzed by neuronal NOS in the presence of 7-MI appeared to be competitive versus both substrate L-arginine (L-arg) and (6R)-5,6,7,8-tetrahydrobiopterin (BH(4)) cofactor. 7-MI only slightly inhibited NADPH oxidase activity and was inactive against the cytochrome c (cyt c) reductase activity of neuronal NOS at concentrations up to 100-fold higher than its IC(50) value for inhibition of citrulline formation. UV/Vis and EPR studies indicated that 7-MI interacts with the oxygenase domain of neuronal NOS (NOS I(oxy)) in an identical manner but with a much lower affinity than 7-nitroindazole (7-NI). These results demonstrate that an indazole derivative bearing an electron-rich substituent in the 7-position is also a NOS I inhibitor and that such a compound presents strong similarities with the mechanism of inhibition of 7-NI.
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PMID:Inhibitory effects and spectral interactions of isomeric methoxyindazoles on recombinant nitric oxide synthases. 1462 74

The present study examined in vitro vasomotor function and expression of enzymes controlling nitric oxide (NO) bioavailability in thoracic aorta of adult male normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) that either remained sedentary (Sed) or performed 6 wk of moderate aerobic exercise training (Ex). Training efficacy was confirmed by elevated maximal activities of both citrate synthase (P = 0.0024) and beta-hydroxyacyl-CoA dehydrogenase (P = 0.0073) in the white gastrocnemius skeletal muscle of Ex vs. Sed rats. Systolic blood pressure was elevated in SHR vs. WKY (P < 0.0001) but was not affected by Ex. Despite enhanced endothelium-dependent relaxation to 10(-8) M ACh in SHR vs. WKY (P = 0.0061), maximal endothelium-dependent relaxation to 10(-4) M ACh was blunted in Sed SHR (48 +/- 12%) vs. Sed WKY (84 +/- 6%, P = 0.0067). Maximal endothelium-dependent relaxation to 10(-4) M ACh was completely restored in Ex SHR (93 +/- 9%) vs. Sed SHR (P = 0.0011). N(omega)-nitro-l-arginine abolished endothelium-dependent relaxation in all groups (P </= 0.0001) and caused equal vasocontraction to maximal ACh in Sed SHR and Ex SHR. Endothelium-independent relaxation to sodium nitroprusside was similar in all groups. Protein levels of endothelial NO synthase were higher in SHR vs. WKY (P = 0.0157) and in Ex vs. Sed (P = 0.0536). Protein levels of the prooxidant NAD(P)H oxidase subunit, gp91phox, were higher in SHR vs. WKY (P < 0.0001) and were diminished in Ex vs. Sed (P = 0.0557). Levels of the antioxidant SOD-1, -2, and catalase enzymes were lower in SHR vs. WKY (all P </= 0.0005) but were not altered by Ex. Thus elevated gp91phox-dependent oxidative stress and reduced antioxidant capacity likely contributed to impaired endothelium-dependent vasorelaxation in Sed SHR. Furthermore, reduced gp91phox-dependent oxidative stress and enhanced endothelial NO synthase-derived NO likely contributed to restored endothelium-dependent vasorelaxation in Ex SHR.
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PMID:Exercise training improves aortic endothelium-dependent vasorelaxation and determinants of nitric oxide bioavailability in spontaneously hypertensive rats. 1475 24

Salt-sensitive hypertension is associated with impaired NO/cGMP signaling. We hypothesized that increased superoxide production by NADPH oxidase and altered endothelial NO synthase (NOS3) phosphorylation determine endothelial dysfunction in hypertension. Experiments tested if NO/cGMP signaling and NOS3 serine phosphorylation are decreased and NADPH oxidase activity is increased in mesenteric arteries from deoxycorticosterone acetate (DOCA)-salt rats compared with arteries from placebo rats. Concentration response curves to phenylephrine were performed in mesenteric arteries in the presence and absence of Nomega-nitro-L-arginine (LNA) and antioxidants to determine the influence of basal NO and superoxide production on vascular tone. LNA increased phenylephrine sensitivity in arteries from placebo, but not DOCA-salt rats, regardless of antioxidant treatment. To determine basal cGMP production, mesenteric arteries were incubated with 3-isobutyl-1-methylxanthine in the presence or absence of LNA, sodium nitroprusside (SNP), antioxidants, or tetrahydrobiopterin. NOS-dependent cGMP production was reduced in arteries from DOCA-salt rats compared with arteries from placebo rats and was not restored by acute treatment with antioxidants or tetrahydrobiopterin. SNP-induced cGMP production was similar between groups as was NADPH oxidase activity, measured by lucigenin chemiluminescence, in mesenteric arteries. Expression and phosphorylation of NOS3 were examined by Western blotting. Phosphorylation of NOS3 was decreased in arteries from DOCA-salt rats compared with placebo at serine residues 1179 and 635. These findings indicate that diminished NO/cGMP signaling in mesenteric arteries from DOCA-salt rats is caused by reduced phosphorylation of NOS3 at serine 1179 and serine 635, rather than NO scavenging by superoxide.
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PMID:Reduced NOS3 phosphorylation mediates reduced NO/cGMP signaling in mesenteric arteries of deoxycorticosterone acetate-salt hypertensive rats. 1499 98

Accumulating evidence suggests that changes in both 5-hydroxytryptamine (5-HT) receptor activity and in the levels of reactive oxygen species (ROS) play an important role in regulating pulmonary artery (PA) vascular responsiveness, particularly in the setting of pulmonary hypertension. Therefore, we hypothesized that increased levels of superoxide enhance 5-HT-induced PA constriction. With the use of a small-vessel bioassay, 5-HT (0.01-10 microM) induced a concentration-dependent vasoconstriction in isolated wild-type murine intrapulmonary arteries (100-150 microm diameter) that was enhanced by both removal of the endothelium and by treatment with either N(G)-nitro-L-arginine methyl ester (30 microM) or xanthine (10 microM) + xanthine oxidase (0.005 U/ml). PA isolated from extracellular superoxide dismutase (EC-SOD) knockout mice also showed enhanced constriction. On the other hand, PA constriction to 5-HT was attenuated by either the addition of GR-127935 (0.1 microM, a selective inhibitor of 5-HT(1B/1D) receptor) or copper/zinc-containing superoxide dismutase (Cu/Zn SOD, 150 U/ml) and in PA isolated from transgenic mice overexpressing human EC-SOD. With the use of both oxidative fluorescent confocal microscopy and lucigenin-enhanced chemiluminescence, superoxide levels were increased significantly after 5-HT-induced PA vasoconstriction. This increase in superoxide levels could be blocked by the exogenous addition of Cu/Zn SOD (150 U/ml) or by apocynin (30 microM, an inhibitor of NADPH oxidase) but was not affected by gp91(phox) knockout mice. Overall, our results are consistent with 5-HT increasing vascular smooth muscle superoxide production via an NADPH oxidase pathway that is independent of gp91(phox), which leads to increases in extracellular superoxide levels, which in turn enhances 5-HT-induced murine pulmonary vasoconstriction.
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PMID:Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction. 1502 Feb 94

Proliferation of endothelial cells plays a crucial role in the process of atherosclerotic plaque destabilization. The major component of oxidized low-density lipoprotein lysophosphatidylcholine (LPC) has been shown to promote endothelial proliferation by increasing the production of reactive oxygen species (ROS). Since K(+) channels are known to control the cell cycle, we investigated the role of Ca(2+)-activated K(+) channels (BK(Ca)) in the regulation of LPC-induced endothelial proliferation and ROS generation. A significant increase of cell growth induced by LPC (20 micromol/l; cell counts (CCs): +87%, thymidin incorporation: +89%; n = 12, P < 0.01) was observed, which was inhibited by the BK(Ca) inhibitor iberiotoxin (IBX; 100 nmol/l), by the NAD(P)H-oxidase inhibitor diphenyleneiodonium (5 micromol/l) and by transfection with antisense (AS) oligonucleotides against NAD(P)H oxidase, whereas N(G)-monomethyl-l-arginine (l-NMMA) further increased LPC-induced cell growth. Using the patch-clamp technique a significant increase of BK(Ca) open-state probability (control: 0.004 +/- 0.002; LPC: 0.104 +/- 0.035; n = 21, P < 0.05) by LPC was observed. Using dichlorofluorescein fluorescence microscopy a significant increase of ROS induced by LPC was reported, that was blocked by IBX and Ca(2+) antagonists. Intracellular Ca(2+) measurements revealed a capacitative Ca(2+) influx caused by LPC. Bioactivity of nitric oxide (NO) was measured using a [(3)H]-cGMP radioimmunoassay. LPC significantly decreased acetylcholine-induced NO synthesis. LPC significantly increased cGMP levels in endothelial cells transfected with AS, which was blocked by IBX. In conclusion, our results demonstrate that LPC activates BK(Ca) thereby increasing ROS production which induces endothelial proliferation. In addition LPC-induced BK(Ca)-activation contributes to increased cGMP levels, if ROS production is prevented by AS.
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PMID:Lysophosphatidylcholine-induced modulation of Ca(2+)-activated K(+)channels contributes to ROS-dependent proliferation of cultured human endothelial cells. 1513 62

Protein levels and polymorphisms of p22(phox) have been suggested to modulate vascular NAD(P)H oxidase activity and vascular production of reactive oxygen species (ROS). We sought to determine whether increasing p22(phox) expression would alter vascular ROS production and hemodynamics by targeting p22(phox) expression to smooth muscle in transgenic (Tg) mice. Aortas of Tg(p22smc) mice had increased p22(phox) and Nox1 protein levels and produced more superoxide and H(2)O(2). Surprisingly, endothelium-dependent relaxation and blood pressure in Tg(p22smc) mice were normal. Aortas of Tg(p22smc) mice produced twofold more nitric oxide (NO) at baseline and sevenfold more NO in response to calcium ionophore as detected by electron spin resonance. Western blot analysis revealed a twofold increase in endothelial NO synthase (eNOS) protein expression in Tg(p22smc) mice. Both eNOS expression and NO production were normalized by infusion of the glutathione peroxidase mimetic ebselen or by crossing Tg(p22smc) mice with mice overexpressing catalase. We have previously found that NO stimulates extracellular superoxide dismutase (ecSOD) expression in vascular smooth muscle. In keeping with this, aortic segments from Tg(p22smc) mice expressed twofold more ecSOD, and chronic treatment with the NOS inhibitor N(G)-nitro-L-arginine methyl ester normalized this, suggesting that NO regulates ecSOD protein expression in vivo. These data indicate that chronic oxidative stress caused by excessive H(2)O(2) production evokes a compensatory response involving increased eNOS expression and NO production. NO in turn increases ecSOD protein expression and counterbalances increased ROS production leading to the maintenance of normal vascular function and hemodynamics.
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PMID:Hemodynamic and biochemical adaptations to vascular smooth muscle overexpression of p22phox in mice. 1547 76

The present study tested the hypothesis that endostatin stimulates superoxide (O2*-) production through a ceramide-mediating signaling pathway and thereby results in an uncoupling of bradykinin (BK)-induced increases in intracellular Ca2+ concentration ([Ca2+]i) from nitric oxide (NO) production in coronary endothelial cells. With the use of high-speed, wavelength-switching, fluorescence-imaging techniques, the [Ca2+]i and NO levels were simultaneously monitored in the intact endothelium of freshly isolated bovine coronary arteries. Under control conditions, BK was found to increase NO production and [Ca2+]i in parallel. When the arteries were pretreated with 100 nM human recombinant endostatin for 1 h, this BK-induced NO production was reduced by 89%, whereas [Ca2+]i was unchanged. With the conversion rate of L-[3H]arginine to L-[3H]citrulline measured, endostatin had no effect on endothelial NO synthase (NOS) activity, but it stimulated ceramide by activation of sphingomyelinase (SMase), whereby O2*-. production was enhanced in endothelial cells. O2*-. scavenging by tiron and inhibition of NAD(P)H oxidase by apocynin markedly reversed the effect of endostatin on the NO response to BK. These results indicate that endostatin increases intracellular ceramide levels, which enhances O2*-. production through activation of NAD(P)H oxidase. This ceramide-O2*-. signaling pathway may contribute importantly to endostatin-induced endothelial dysfunction.
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PMID:Endostatin uncouples NO and Ca2+ response to bradykinin through enhanced O2*- production in the intact coronary endothelium. 1547 85

Increased oxidative stress may play a key role in the progressive deterioration of pancreatic beta-cells and the development of diabetes. However, the underlying mechanism is not well understood. Exposure of pancreatic beta-cell line, MIN6 cells, to elevated glucose level for 2h induced an increase in reactive oxygen species (ROS) production, as evaluated by the staining of 2',7'-dichlorofluorescein diacetate. This effect was completely blocked by NAD(P)H oxidase inhibitor (diphenylene iodonium) and protein kinase C (PKC) inhibitor (calphostin C), but not affected by other flavoprotein inhibitors (rotenone, oxypurinol, or l-N-monomethyl arginine). Glibenclamide also stimulated ROS production in a dose-dependent manner. This effect was again blocked by diphenylene iodonium and calphostin C. In conclusion, insulin secretagogues, both glibenclamide and elevated glucose level, stimulated ROS production in beta-cells through a PKC-dependent activation of NAD(P)H oxidase. This mechanism may be a novel therapeutic target for preventing the progression of beta-cell deterioration.
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PMID:Sulfonylurea as well as elevated glucose levels stimulate reactive oxygen species production in the pancreatic beta-cell line, MIN6-a role of NAD(P)H oxidase in beta-cells. 1556 52

Insulin resistance (IR) and associated hyperinsulinemia are major risk factors for coronary artery disease. Mechanisms linking hyperinsulinemia to coronary vascular dysfunction in IR are unclear. We evaluated insulin-induced vasodilation in isolated small coronary arteries (SCA; approximately 225 microm) of Zucker obese (ZO) and control Zucker lean (ZL) rats. Vascular responses to insulin (0.1-100 ng/ml), ACh (10(-9)-10(-5) mol/l), and sodium nitroprusside (10(-8)-10(-4) mol/l) were assessed in SCA by measurement of intraluminal diameter using videomicroscopy. Insulin-induced dilation was decreased in ZO compared with ZL rats, whereas ACh and sodium nitroprusside elicited similar vasodilations. Pretreatment of arteries with SOD (200 U/ml), a scavenger of reactive oxygen species (ROS), restored the vasorelaxation response to insulin in ZO arteries, whereas ZL arteries were unaffected. Pretreatment of SCA with N-nitro-L-arginine methyl ester (100 micromol/l), an inhibitor of endothelial nitric oxide (NO) synthase (eNOS), elicited a vasoconstrictor response to insulin that was greater in ZO than in ZL rats. This vasoconstrictor response was reversed to vasodilation in ZO and ZL rats by cotreatment of the SCA with SOD or apocynin (10 micromol/l), a specific inhibitor of vascular NADPH oxidase. Lucigenin-enhanced chemiluminescence showed increased basal ROS levels as well as insulin (330 ng/ml)-stimulated production of ROS in ZO arteries that was sensitive to inhibition by apocynin. Western blot analysis revealed increased eNOS expression in ZO rats, whereas Mn SOD and Cu,Zn SOD expression were similar to ZL rats. Thus IR in ZO rats leads to decreased insulin-induced vasodilation, probably as a result of increased production of ROS by vascular NADPH oxidase, leading to decreased NO bioavailability, despite a compensatory increase in eNOS expression.
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PMID:Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species. 1565 Jan 57


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