Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 (ET-1) is implicated in the development of endothelial dysfunction through the generation of reactive oxygen species by NADPH oxidase activation. Interleukin-10 (IL-10) is an antiinflammatory cytokine that stimulates nitric oxide production, decreases superoxide production, and restores endothelial integrity after vascular injury. In this study, we tested whether IL-10 attenuates ET-1-induced endothelial dysfunction by improving acetylcholine (ACh)-induced relaxation of cultured murine aortic rings. Aortic rings (2 mm long) of C57BL/6 mice were incubated in 2 mL DMEM containing 120 U/mL penicillin and 120 microg/mL streptomycin in the presence of one of 4 treatments: vehicle (deionized water), ET-1 (100 nmol/L), recombinant mouse IL-10 (300 ng/mL), or a combination of both ET-1 and IL-10. After incubation at 37 degrees C for either 1 or 6 h (short-term exposure) or 22 h (overnight exposure), rings were mounted in a wire myograph and stretched to a passive force of 5 mN. Endothelium-dependent vasorelaxation was assessed by constructing cumulative concentration-response curves to ACh (0.001-10 micromol/L) during 10 mumol/L phenylephrine (PE)-induced contraction. Short-term exposure of ET-1 did not result in an impairment of ACh-induced relaxation. Overnight exposure of aortic rings to ET-1 resulted in a statistically significant endothelial dysfunction characterized by a reduced maximal relaxation response to ACh compared with that of untreated rings (Emax 57% +/- 3% versus 82% +/- 4%). IL-10 treatment restored ACh-induced relaxation (Emax 77% +/- 3%). Western blotting showed decreased eNOS expression in response to ET-1, whereas vessels treated with a combination of ET-1 and IL-10 showed increased expression of eNOS. Immunohistochemical analysis showed decreased eNOS expression in ET-1-treated vessels compared with those treated with both ET-1 and IL-10. We conclude that, in murine aorta, the antiinflammatory cytokine IL-10 prevents impairment in endothelium-dependent relaxation induced in response to long-term incubation with ET-1 via normalization of eNOS expression.
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PMID:Restoration of endothelin-1-induced impairment in endothelium-dependent relaxation by interleukin-10 in murine aortic rings. 1875 4

Endothelial cells in vivo are constantly exposed to shear associated with blood flow and altered shear stress elicits cellular responses (mechanotransduction). This review describes the role of shear sensors and signal transducers in these events. The major focus is the response to removal of shear as occurs when blood flow is compromised (i.e., ischemia). Pulmonary ischemia studied with the isolated murine lung or flow adapted pulmonary microvascular endothelial cells in vitro results in endothelial generation of reactive oxygen species (ROS) and NO. The response requires caveolae and is initiated by endothelial cell depolarization via K(ATP) channel closure followed by activation of NADPH oxidase (NOX2) and NO synthase (eNOS), signaling through MAP kinases, and endothelial cell proliferation. These physiological mediators can promote vasodilation and angiogenesis as compensation for decreased tissue perfusion.
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PMID:Lung ischemia: a model for endothelial mechanotransduction. 1898 55

Coronary, vascular and perivascular inflammation in rats following MR (mineralocorticoid receptor) activation plus salt are well-characterized precursors for the appearance of cardiac fibrosis. Endogenous corticosterone, in the presence of the 11betaHSD2 (11beta hydroxysteroid dehydrogenase type 2) inhibitor CBX (carbenoxolone) plus salt, produces similar inflammatory responses and tissue remodelling via activation of MR. MR-mediated oxidative stress has previously been suggested to account for these responses. In the present study we thus postulated that when 11betaHSD2 is inhibited, endogenous corticosterone bound to unprotected MR in the vessel wall may similarly increase early biomarkers of oxidative stress. Uninephrectomized rats received either DOC (deoxycorticosterone), CBX or CBX plus the MR antagonist EPL (eplerenone) together with 0.9% saline to drink for 4, 8 or 16 days. Uninephrectomized rats maintained on 0.9% saline for 8 days served as controls. After 4 days, both DOC and CBX increased both macrophage infiltration and mRNA expression of the p22(phox) subunit of NADPH oxidase, whereas CBX, but not DOC, increased expression of the NOX2 (gp91(phox)) subunit. eNOS [endothelial NOS (NO synthase)] mRNA expression significantly decreased from 4 days for both treatments, and iNOS (inducible NOS) mRNA levels increased after 16 days of DOC or CBX; co-administration of EPL inhibited all responses to CBX. The responses characterized over this time course occurred before measurable increases in cardiac hypertrophy or fibrosis. The findings of the present study support the hypothesis that endogenous corticosterone in the presence of CBX can activate vascular MR to produce both inflammatory and oxidative tissue responses well before the onset of fibrosis, that the two MR ligands induce differential but overlapping patterns of gene expression, and that elevation of NOX2 subunit levels does not appear necessary for full expression of MR-mediated inflammatory and fibrogenic responses.
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PMID:Mediators of mineralocorticoid receptor-induced profibrotic inflammatory responses in the heart. 1899 85

Endothelial cells in vivo are constantly exposed to mechanical forces such as cyclic strain. In endothelial cells, Nox4-containing NAD(P)H oxidase complexes have been identified as major sources of superoxide anion (.O(2)(-)) formation. In this study, we analyzed the effect of cyclic strain on endothelial ROS formation by electron paramagnetic resonance spectroscopy, cytochrome c assay, and dihydroethidium fluorescence, on NO formation by Griess reaction and on gene expression by RT-PCR and Western blot. Primary cultures of human umbilical vein endothelial cells were exposed to 2-18% cyclic strain for up to 24 h using the Flexercell system. Long-term application of 5-12% cyclic strain downregulated Nox4 expression and ROS formation in a time-dependent manner. Downregulation of Nox4 was further confirmed by promoter analysis using dual-luciferase assay. Cu/Zn SOD, MnSOD, and catalase expression was decreased after application of chronic 12% cyclic strain. In contrast, endothelial NO formation and eNOS were increased by cyclic strain. Strain-dependent Nox4 downregulation was abolished by eNOS inhibition with L-NAME. In conclusion, physiological levels of cyclic strain downregulate Nox4 expression and superoxide anion formation. This novel mechanism might contribute to a vasoprotective balance between NO and superoxide anions in response to physiological mechanical stimulation of endothelial cells.
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PMID:Long-term cyclic strain downregulates endothelial Nox4. 1930 65

This study was conducted to examine the role of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in monocyte adhesion-induced redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in endothelial cells (ECs). LOX-1 was blocked by an antibody-neutralizing LOX-1 TS92 or small interfering RNA. In cultured human aortic ECs, monocyte adhesion activated Rac1 and p47(phox), and increased NADPH oxidase activity and reactive oxygen species (ROS) generation within 30 min and NF-kappaB phosphorylation within 1 h, resulting in redox-sensitive gene expression. Akt and eNOS phosphorylation was induced 15 min after adding monocytes and returned to control level after 30 min, whereas NO production was not altered by monocyte adhesion. Blockade of LOX-1 blunted the monocyte adhesion-triggered redox-sensitive signaling pathway and Akt/eNOS phosphorylation in ECs. Both endothelial intracellular Ca2+ mobilization and Ca2+ influx caused by monocyte attachment were markedly attenuated by pretreatment of ECs with TS92. This suggests that LOX-1 is involved in redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in monocyte adhesion to ECs independent of oxidized low-density lipoprotein (ox-LDL). Furthermore, blockade of Ca2+ inhibited monocyte adhesion-triggered Rac1 and p47(phox) activation and ROS generation in ECs, whereas Ca2+ signaling was suppressed by blockade of NADPH oxidase and ROS generation. Finally, TS92 blocked the monocyte adhesion to ECs stimulated with or without tumor necrosis factor-alpha or ox-LDL. We provide evidence that LOX-1 plays a role in redox-sensitive, Akt/eNOS and Ca2+ signaling pathways in monocyte adhesion to ECs independent of the ox-LDL-LOX-1 axis.
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PMID:Role of LOX-1 in monocyte adhesion-triggered redox, Akt/eNOS and Ca2+ signaling pathways in endothelial cells. 1945 49

Arachidonic acid can act as a second messenger regulating many cellular processes among which is nitric oxide (NO) formation. The aim of the present study was to investigate the molecular mechanisms involved in the arachidonic acid effect on platelet NO level. Thus NO, cGMP and superoxide anion level, the phosphorylation status of nitric oxide synthase, the protein kinase C (PKC), and NADPH oxidase activation were measured. Arachidonic acid dose-dependently reduced NO and cGMP level. The thromboxane A(2) mimetic U46619 behaved in a similar way. The arachidonic acid or U46619 effect on NO concentration was abolished by the inhibitor of the thromboxane A(2) receptor SQ29548 and partially reversed by the PKC inhibitor GF109203X or by the phospholipase C pathway inhibitor U73122. Moreover, it was shown that arachidonic acid activated PKC and decreased nitric oxide synthase (eNOS) activities. The phosphorylation of the inhibiting eNOSthr495 residue mediated by PKC was increased by arachidonic acid, while no changes at the activating ser1177 residue were shown. Finally, arachidonic acid induced NADPH oxidase activation and superoxide anion formation. These effects were greatly reduced by GF109203X, U73122, and apocynin. Likely arachidonic acid reducing NO bioavailability through all these mechanisms could potentiate its platelet aggregating power.
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PMID:The arachidonic acid effect on platelet nitric oxide level. 1961 63

In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering the membrane association of these molecules, statins affect intracellular positioning and hence activity of a multitude of substances. These include eNOS(endothelial NO synthase), which produces NO (inhibited by Rho), and NADPH oxidase, which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of NO while decreasing superoxide production. A total of 40 hypercholesterolaemic patients were randomized to treatment with either atorvastatin or placebo; 20 normolipidaemic patients were also studied. Platelet nitrite, NO and superoxide were examined as was the cellular distribution of the GTPases Rho and Rac at baseline and after 8 weeks of treatment.Following atorvastatin therapy, platelet NO was increased (3.2 pmol/10(8) platelets) and superoxide output was attenuated [-3.4 pmol min(-1) (10(8) platelets)(-1)] when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets, implying reduced activity. In conclusion, the results of the present study show altered NO/superoxide production following statin therapy. A potential mechanism for this is the change in the distribution of intracellular GTPases, which was considered to be secondary to decreases in isoprenoid intermediates, suggesting that the activity of the former had been affected by atorvastatin.
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PMID:Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia. 1974 72

We studied whether Pycnogenol (PYC) may attenuate the development of experimental streptozotocin-induced diabetic cardiomyopathy in rat. In addition, we aimed to study whether PYC affects cardiac oxidative stress and the protein expression of reactive oxygen species (ROS)-producing molecules (gp91(phox)-containing NADPH oxidase and NO-signalling proteins). Experimental diabetes mellitus was manifested by hyperglycaemia and impaired cardiac function estimated using left ventricular catheterisation in vivo. PYC lowered fasting plasma glucose and normalized basal cardiac function. Excessive oxidative stress in streptozotocin (STZ) hearts, evidenced by 40% increase (P < 0.05) of thiobarbituric acid reactive substances (TBARS) concentration, was associated with increased expression of gp91(phox) (by 75%, P < 0.05), iNOS (by 40%, P < 0.05) and alpha-tubulin (by 49%, P < 0.05), but unchanged expression of eNOS and its alosteric regulators, as compared to CON. PYC failed to affect these expression abnormalities. Our study shows that PYC corrects diabetic cardiac dysfunction, probably by its metabolic and direct radical scavenging activity without affecting the molecular maladaptations of ROS-producing enzymes and cytoskeletal components.
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PMID:Pycnogenol improves left ventricular function in streptozotocin-induced diabetic cardiomyopathy in rats. 1995 51

Previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cells (EPCs) numbers and impairs functional activity. Atorvastatin, HMG-CoA inhibition has been showed to have protective effects on EPCs. Recent studies have demonstrated that reduced EPCs numbers and activity are associated with EPCs apoptosis. However, the protective mechanisms of atorvastatin on HHcy-induced EPCs apoptosis remain to be determined. This study was designed to examine the effect of atorvastatin on homocysteine-induced reactive oxygen species (ROS) production and apoptosis in EPCs. EPCs were isolated from peripheral blood and characterized, then challenged with Hcy (50-500 micromol/L) in the presence or absence of atorvastatin (0.01-1 micromol/L) or various stress signaling inhibitors, including mevalonate (100 micromol/L), antioxidants N-acetyl cysteine (NAC, 10 micromol/L), the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium (DPI 10 micromol/L), the eNOS inhibitor N(G)mono-methyl-l-arginine LNMA (1mmol/L), and the p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB203580 (10 micromol/L). Apoptosis was evaluated by FACS analysis and cell viability was determined by MTT assay. ROS were detected by 2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFH-DA). NADPH oxidases were evaluated with lucigenin-enhanced chemiluminescence. Expression of Nox4 mRNA and p-p38MAPK protein was measured by RT-PCR and Western blot analysis, respectively. Our data revealed that atorvastatin significantly suppressed Hcy-induced ROS accumulation and EPCs apoptosis. Atorvastatin also antagonized homocysteine-induced activation of NADPH oxidase and overexpression of Nox4 mRNA and p-p38MAPK protein. Similar effects occurred with EPCs transfected with Nox4 siRNA. These findings demonstrated that atorvastatin may inhibit Hcy-induced NADPH oxidase activation, ROS accumulation, and EPCs apoptosis through Nox4/p38MAPK dependent mechanisms, all of which may contribute to atorvastatin-induced beneficial effects on EPCs function.
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PMID:Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK. 2001 84

The aim of the present study was to examine the effect of an early stage of streptozotocin-induced diabetes on the mechanism(s) of endothelium-dependent relaxation. Diabetes was induced by a single injection of streptozotocin (48 mg/kg iv), and the ACh-induced relaxation of rat carotid arteries was examined 6 wk later. A diabetes-induced increase in superoxide levels, determined by L-012-induced chemiluminescence, from carotid arteries was associated with endothelial nitric oxide (NO) synthase (eNOS) uncoupling and increased catalytic subunit of NADPH oxidase expression. The sensitivity and maximum response to ACh were similar in normal and diabetic rats despite a decrease in NO release detected by 4-amino-5-methylamino-2',7'-difluorofluorescein. In normal rats, N-nitro-l-arginine (100 microM) plus 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (10 microM), to inhibit NOS and soluble guanylate cyclase (sGC), respectively, abolished ACh-induced relaxation, whereas in diabetic rats, the maximum relaxation to ACh was attenuated (maximum relaxation: 25 + or - 5%), but not abolished, by that treatment. The remaining ACh-induced relaxation was abolished by NO scavengers, cupric chloride (to degrade nitrosothiols), or blockers of endothelial K(+) channels. Western blot analysis of the carotid arteries indicated that diabetes significantly increased the expression of eNOS but decreased the proportion of eNOS expressed as the dimer. These findings demonstrate that in early diabetes, ACh-induced relaxation is maintained but is resistant to NOS inhibition. In early diabetes, nitrosothiol-mediated opening of K(+) channels may act in conjunction with NO stimulation of sGC to maintain endothelium-dependent relaxation despite the increase in vascular superoxide levels.
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PMID:Short-term type 1 diabetes alters the mechanism of endothelium-dependent relaxation in the rat carotid artery. 2054 87


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