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:1.5.1.19 (NOS)
7,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical and experimental studies indicate that nonimmunologic factors may modulate the alloreactivity of a renal transplant. Nitric oxide (NO) is an essential modulator of endothelial function. It was postulated that, in renal allografts, inhibition of constitutive NO synthase may lead to an aggravation of immunologic damage to endothelia and therefore may enhance dysfunction of the graft. Male Lewis (RT1l) rats received syngeneic or allogeneic Brown Norway (RT1n) renal grafts and were treated with cyclosporin A (CyA) or with CyA and an NO synthase blocker (NOS-B): N omega-nitro-L-arginine (L-NNA) or NG-monomethyl-L-arginine (L-NMMA). CyA was given at a dose of 3.5 mg/kg body weight for 14 days and the NOS-B at a dose of 66 mg/L drinking water for up to 28 days postoperatively. Animals (N = 6/group) were studied at 4 to 7, 14, and 28 days posttransplantation. Four to 5 days posttransplantation, renal blood flow and glomerular filtration rate of allogeneic grafts did not differ between animals treated only with CyA and those treated with CyA and NOS-B. Mean arterial pressure was significantly elevated by NOS-B (CyA+L-NNA: 115 +/- 13 versus CyA: 78 +/- 16 mm Hg). Combined NOS-B and CyA administration led to a pronounced increase in vascular and tubulointerstitial damage. The number of mononuclear cells in vessels, glomeruli, and tubulointerstitium increased significantly in allografts upon treatment with NOS-B. During NOS-B administration, adhesion molecules (intracellular adhesion molecule-1; leukocyte-function-associated molecules-1 alpha and-beta) were strongly expressed in endothelial and leukocytic cells of the allograft. A pronounced positivity for mRNA and protein of cytokines tumor necrosis factor-alpha and transforming growth factor-beta could be demonstrated in the inflammatory infiltrate. With L-NNA treatment, the total vascular injury index was 10-fold higher (14 days posttransplantation, CyA+L-NNA: 59.8 +/- 11.7 versus CyA: 6.0 +/- 1.8; p < 0.05). The tubulointerstitial damage score rose more than 2.5-fold after CyA and L-NNA therapy (28 days posttransplantation: CyA+L-NNA: 83 +/- 1 versus CyA:29 +/- 1). L-NNA was more potent than L-NMMA at the dosages used. Thus, pronounced vascular leukostasis, vasculitis, and T-cell and monocyte infiltration of the tubulointerstitium led to a severe damage of the allograft under therapy with CyA and NOS-B. Inhibition of NO synthesis may aggravate alloreactive immunemediated injury in kidney transplants acting primarily by a disturbance of endothelial function.
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PMID:Enhanced renal allograft rejection by inhibitors of nitric oxide synthase: a nonimmunologic influence on alloreactivity. 878 Jan 67

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.
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PMID:Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase. 935 74

Expression of the inducible isoform of nitric oxide synthase (iNOS) is stimulated by cytokines in human epithelial cells. This work indicates that incubation of human umbilical cord endothelial cells with combinations of interleukin-1beta, tumor necrosis factor alpha, and interferon-gamma stimulated the synthesis of iNOS mRNA, as detected by reverse transcriptase-polymerase chain reaction. It is important to note that 50, 100, and 200 microM hydrogen peroxide was able to stimulate iNOS directly. Furthermore, 100 microM H2O2 enhanced synthesis of the oxidation products, nitrite (NO2-) and nitrate (NO3-) at 12 and 36 h. iNOS protein, detected by Western blot analysis, as well as L-citrulline levels, were also increased. When endothelial cell monolayers were incubated for 1 h with 100 microM H2O2 and subsequently with cytokines, iNOS mRNA was further augmented. Under the same conditions, we regularly observed an inhibition (25%) of intercellular adhesion molecule-1 (ICAM-1/CD54) expression. The latter was reversed when the NOS inhibitor N(G)-monomethyl-L-arginine was added, as shown by flow cytometry. These data suggest a specific effect of endogenous hydroperoxides on the biosynthesis and processing of the human endothelial iNOS isoform. We propose that H2O2 induces a temporary NO-dependent modulation of adhesion molecule expression to limit the tissue destruction that accompanies the vascular recruitment of leukocytes.
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PMID:Regulation of ICAM-1/CD54 expression on human endothelial cells by hydrogen peroxide involves inducible NO synthase. 1073 92

The authors studied whether cyclic AMP (cAMP), a widespread regulator of inflammation, modulates the cytokine-mediated expression of the intercellular adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), and the inflammatory nitric oxide synthase 2 (NOS-2), in primary and immortalized brain endothelial cell cultures (GP8.3 cell line). When measured by enzyme-linked immunosorbent assay (ELISA), ICAM-1 was constitutively expressed and was up-regulated twofold by interleukin-1beta, with no effect of interferon-gamma. The NOS-2 activity, assessed by nitrite accumulation, was absent from untreated cultures but was induced by interleukin-1beta and interferon-gamma acting synergistically. Stimulation of cAMP-dependent pathways with forskolin or dibutyryl cAMP decreased ICAM-1 protein expression, whereas it increased NOS-2 protein expression. For both ICAM-1 and NOS-2, mRNA expression correlated with protein expression. Blockade of NOS activity with L-N-monomethylargiuine (L-NMMA) did not alter ICAM-1 expression, indicating that the nitric oxide released by NOS-2 did not cause the down-regulation of ICAM-1. Analysis of NFKB activation indicated that cAMP acted through a mechanism other than inhibition of nuclear translocation of NFKB. The authors conclude that cAMP modulates the expression of proinflammatory molecules in brain endothelium. This suggests that inflammatory processes at the blood-brain barrier in vivo may be regulated by perivascular neurotransmitters via cAMP.
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PMID:Cyclic adenosine monophosphate regulates the expression of the intercellular adhesion molecule and the inducible nitric oxide synthase in brain endothelial cells. 1077 13

Insulin exerts a vasodilatory effect through the release of nitric oxide (NO) from the endothelium. We have recently demonstrated that insulin also inhibits the expression of intracellular adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1), 2 major proinflammatory mediators, by human aortic endothelial cells (HAEC) and the proinflammatory mediator, nuclear factor (NF-kappa B), in the nucleus in parallel with an increase in endothelial nitric oxide synthase (e-NOS) expression. The inhibition of ICAM-1 by insulin is NO dependent. Because tumor necrosis factor-alpha (TNF-a ) is proinflammatory and may thus inhibit the action of insulin at the endothelial cell level, we have now investigated whether TNF-a affects (1) insulin receptor content; (2) insulin receptor (IR) autophosphorylation induced by insulin, and (3) e-NOS expression by the endothelial cells. TNF-alpha (1 to 5 ng/mL) caused e-NOS inhibition in a dose-dependent fashion as measured by Western blotting. This inhibition was reduced with insulin addition. TNF-alpha also inhibited tyrosine autophosphorylation of the IR in HAEC induced by insulin and reduced IR beta-subunit protein expression in HAEC. These effects of insulin and TNF-alpha were independent of cell proliferation, as cell counts did not change with insulin or TNF-alpha. Our data demonstrate that TNF-alpha may exert its effect by inhibiting IR autophosphorylation in HAEC and also by reducing IR protein (IRP) expression. Although the inhibition of IR autophosphorylation by TNF-alpha is known to occur at the adipocyte level, the data on the inhibitory effect of TNF-alpha on insulin-induced e-NOS expression and IRP contents are novel.
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PMID:Tumor necrosis factor-alpha inhibits insulin-induced increase in endothelial nitric oxide synthase and reduces insulin receptor content and phosphorylation in human aortic endothelial cells. 1191 59

The objective of this study was to determine whether absence of endothelial nitric oxide synthase (eNOS) affects the expression of cell surface adhesion molecules in endothelial cells. Murine lung endothelial cells (MLECs) were prepared by immunomagnetic bead selection from wild-type and eNOS knockout mice. Wild-type cells expressed eNOS, but eNOS knockout cells did not. Expression of neuronal NOS and inducible NOS was not detectable in cells of either genotype. Upon stimulation, confluent wild-type MLECs produced significant amounts of NO compared with N(omega)-monomethyl-l-arginine-treated wild-type cells. eNOS knockout and wild-type cells showed no difference in the expression of E-selectin, P-selectin, intracellular adhesion molecule-1, and vascular cell adhesion molecule-1 as measured by flow cytometry on the surface of platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31)-positive cells. Both eNOS knockout and wild-type cells displayed the characteristics of resting endothelium. Adhesion studies in a parallel plate laminar flow chamber showed no difference in leukocyte-endothelial cell interactions between the two genotypes. Cytokine treatment induced endothelial cell adhesion molecule expression and increased leukocyte-endothelial cell interactions in both genotypes. We conclude that in resting murine endothelial cells, absence of endothelial production of NO by itself does not initiate endothelial cell activation or promote leukocyte-endothelial cell interactions. We propose that eNOS derived NO does not chronically suppress endothelial cell activation in an autocrine fashion but serves to counterbalance signals that mediate activation.
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PMID:Role of endothelial nitric oxide synthase in endothelial activation: insights from eNOS knockout endothelial cells. 1507 19

Vascular endothelial-cadherin (VE-cadherin), a calcium-dependent homotypic adhesion molecule, contributes to endothelial assembly and VEGF-mediated survival during angiogenesis. In human term placentas, villous vessels and extravillous cytotrophoblasts express VE-cadherin. Therefore, the purpose of this study was to examine if VEGF modulated placental development by increasing the expression of VE-cadherin in rat placentas. Placental tissues from rats on gestation days 14 (G14), 18 (G18) and 21 (G21) were used. Western blot analysis and immunohistochemistry were performed to detect the protein abundance and the distribution of VE-cadherin. A nitric oxide analyzer was used to measure the released nitric oxide (NO) from placental explant culture. With the progression of pregnancy, the abundance of VE-cadherin and the intensity of the immunoreactive staining for VE-cadherin in endovascular trophoblasts and labyrinth trophoblasts were decreased. In explant culture, VEGF (0.01-1.0 ng/ml) increased the protein abundance of VE-cadherin. SNP (an NO donor) or L-arginine (substrate for eNOS) induced the expression of VE-cadherin with the increase of NO production. L-NAME (a NOS inhibitor) reduced the VEGF-increased expression and L-arginine reversed the inhibitory effect of L-NAME. In conclusion, VEGF plays an important role in placental development by the induction of VE-cadherin in trophoblasts, which, in part, maintains the survival of labyrinth trophoblast in rat placentas.
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PMID:Induction of VE-cadherin in rat placental trophoblasts by VEGF through a NO-dependent pathway. 1570 25

Sphingosine 1-phosphate (S1P) stimulates expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in human umbilical vein endothelial cells. S1P-induced actions were associated with nuclear factor kappa-B activation and inhibited by pertussis toxin as well as by antisense oligonucleotides specific to S1P receptors, especially, S1P(3). S1P also stimulated endothelial nitric oxide synthase (eNOS) and its activation was markedly inhibited by the antisense oligonucleotide for the S1P(1) receptor rather than that for the S1P(3) receptor. The dose-response curve of S1P to stimulate adhesion molecule expression was shifted to the left in the presence of the phosphatidylinositol 3-kinase inhibitor wortmannin and the NOS inhibitor Nomega-nitro-l-arginine methyl ester. NO donor S-nitroso-N-acetylpenicillamine inhibited S1P-induced adhesion molecule expression. Moreover, tumor necrosis factor-alpha-induced adhesion molecule expression was markedly inhibited by S1P in a manner sensitive to inhibitors for PI3-K and NOS. These results suggest that S1P receptors are coupled to both stimulatory and inhibitory pathways for adhesion molecule expression. The stimulatory pathway involves nuclear factor kappa-B and inhibitory one does phosphatidylinositol 3-kinase and NOS.
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PMID:Sphingosine 1-phosphate receptors mediate stimulatory and inhibitory signalings for expression of adhesion molecules in endothelial cells. 1611 67

Resveratrol, a polyphenolic phytoaxelin present in red wine, has been suggested to protect against atherosclerosis and cardiovascular disease because of its antioxidant effects. Intercellular adhesion molecule (ICAM-1), induced by cytokines, has been hypothesized to play a role in the early events during atherosclerosis. In this study we tested the effects of resveratrol upon both IL-6-induced ICAM-1 gene expression and its underlying signaling pathways in endothelial cells (ECs). Resveratrol was found to inhibit both TNFalpha- and IL-6-induced ICAM-1 gene expression at the promoter, transcriptional and protein levels. Resveratrol also abrogates the tyr705 phosphorylation of STAT3 in IL-6-treated ECs, in a dose- and time-dependent manner. Although quercetin had similar effects, resveratrol showed higher inhibitory properties following 2-4 h pretreatments. Resveratrol has been shown to induce the activity of endothelial nitric oxide synthase (eNOS) and increase NO production. Consistent with this, the treatment of ECs with a NO donor (SNAP) reduces IL-6-induced STAT3 phosphorylation. Conversely, exposure of ECs to a NOS inhibitor reversed the effects of resveratrol upon IL-6-induced STAT3 phosphorylation. Furthermore, ECs transfected with constitutively active Rac1 (RacV12) showed increases in ICAM-1 promoter activity, intracellular reactive oxygen species (ROS) levels and STAT3 phosphorylation, and these increases were attenuated by resveratrol treatment. In summary, we demonstrate for the first time that resveratrol inhibits IL-6-induced ICAM-1 gene expression, in part, by interfering with Rac-mediated pathways via the attenuation of STAT3 phosphorylation. This study therefore provides important new insights that may contribute to the proposed beneficial effects of resveratrol in endothelial responses to cytokines during inflammation.
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PMID:Resveratrol suppresses IL-6-induced ICAM-1 gene expression in endothelial cells: effects on the inhibition of STAT3 phosphorylation. 1615 Apr 60

The aim of this study was to assess paclitaxel resistant-epithelial ovarian carcinoma (EOC) cells for cellular morphology, motility, and molecular changes consistent with epithelial-mesenchymal transition (EMT). The human EOC cell lines NOS-2, TAOV and SKOV-3 were continuously exposed to increasing doses of paclitaxel to establish three stable cell lines resistant to paclitaxel (NOS-PR, TAOV-PR, and SKOV-PR cells, respectively). Using these cell lines, cellular functions such as motility, invasive ability, and proliferative potential were assessed. Several molecules involved in EMT or cell invasiveness were assessed using Western blot analysis. In a peritoneal metastasis model using mice inoculated with NOS-2 or NOS-PR cells, we investigated the differences of peritoneal dissemination and survival time. NOS2-PR cells showed phenotypic changes consistent with EMT; with spindle-shaped morphology and enhanced pseudopodia formation. Western blot analysis revealed decreased expression of the epithelial adhesion molecule, E-cadherin and an increase in mesenchymal markers such as vimentin, fibronectin and smooth-muscle actin in NOS-PR cells compared to NOS-2 cells. The NOS2-PR cells displayed increased expression of Snail and Twist, EMT-regulatory transcription factors. Migratory potential in a wound assay and metastatic potential to the peritoneum of mice were markedly enhanced in NOS2-PR cells compared to NOS-2 cells. These data suggest that there is a possible link between chronic paclitaxel-resistance and induction of the EMT in EOC cells. It is possible that therapeutic benefits such as the restoration of chemosensitivity or suppression of metastasis will be enabled by gaining further insight into the mechanisms underlying chemoresistance and EMT.
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PMID:Chemoresistance to paclitaxel induces epithelial-mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. 1761 83


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