Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4 serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4 is also a limiting factor for NOS2 expression. In this study we show that BH4 availability can also play a modulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Supplementing HMC with the BH4 donor sepiapterin potentiated IL-1beta/TNF-alpha-induced COX-2 expression by approximately 2-fold. This effect was abolished by methotrexate. In contrast, the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ did not block sepiapterin amplification of COX-2 expression. Moreover, sepiapterin was found to modulate the tyrosine phosphorylation of several cellular substrates, an early event which occurred well before the induction of NOS2 could be evidenced. These findings suggest a role for BH4 in the modulation of mesangial cell responses to pro-inflammatory stimuli.
 ...
PMID:Tetrahydrobiopterin modulates cyclooxygenase-2 expression in human mesangial cells. 940 25

The roles of nitric oxide derived from either the constitutive endothelial NO synthase (eNOS or NOS3) or the inducible NOS (iNOS or NOS2) in hepatic injury during endotoxemia remain controversial. To investigate this further, rats received a bolus of lipopolysaccharide (LPS) following implantation of osmotic pumps containing one of two nonselective NOS inhibitors (NMA or NAME), one of two inducible NOS inhibitors (NIL or AG), or saline. The inhibitors were infused continuously into the liver via the portal vein. Treatment of LPS-injected rats with NMA and NAME resulted in 106 and 227% increases, respectively, in circulating hepatic enzyme levels compared to LPS-treated control rats. In contrast, infusion of the iNOS-selective inhibitors had no effect on the LPS-induced hepatic necrosis. In rats receiving NAME, LPS induced greater neutrophil infiltration and ICAM-1 expression than in the LPS + saline group, whereas NIL infusion did not. The increased hepatic necrosis and PMN infiltration in the LPS + NAME group was partially prevented by a simultaneous infusion of a liver-selective NO donor. Inhibition of PMN accumulation using an anti-ICAM-1 antibody or by PMN depletion using vinblastine pretreatment, however, did not reverse the increased necrosis with NAME infusion during endotoxemia. In contrast to the assessment for necrosis, increased apoptosis was observed in the livers of LPS-treated rats receiving infusions of either NAME or NIL, but not with LPS alone. These data indicate that NO produced by eNOS may be adequate to prevent necrosis by a mechanism independent of PMN, while induced NO appears to prevent apoptosis.
 ...
PMID:Differential effects of nonselective nitric oxide synthase (NOS) and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and neutrophil accumulation during endotoxemia. 944 11

Induction of nitric oxide synthase (NOS2, also designated as iNOS) in the heart is known to occur in response to various stimuli. It is not known, however, whether in vivo hypoxia leads to cardiac NOS2 induction. We thus investigated the effects of normobaric hypoxia (10% O(2)for 8, 15 and 21 days) on NOS2 protein expression and enzyme activity in rat right ventricle (RV) and left ventricle (LV). Chronic hypoxia induced RV hypertrophy: the RV weight to body weight ratio was increased by 45% upon 15 days of exposure, with no change thereafter and no change in left ventricular (LV) weight. Treatment of hypoxic rats with l -NAME for 1 month decreased pulmonary artery pressure and RV hypertrophy compared to hypoxic non-treated rats. NOS2 activity detected by [(3)H]l -arginine to [(3)H]l -citrulline conversion increased in RV during hypoxia, with a maximum at 15 days (+161% of control rats P<0.05), whereas it increased less (by 60%) in LV. In parallel, after 15 days of hypoxia there was a three-fold increase in NOS2 protein abundance detected by Western blotting using an isoform-specific antibody in the RVs (two-fold increase in the LV). Immunochemistry with the specific antibody demonstrated the expression in cardiomyocytes isolated from both ventricles of normoxic and hypoxic rats. Protein kinase C (PKC) content and activity was unchanged in LV of hypoxic rats, but increased in RV as compared with normoxic rats. These results clearly show that, in the heart, NOS2 is upregulated by hypoxia with an expression in cardiomyocytes of both ventricles. In addition, NOS2 is more inducible in the right hypertrophied ventricle than in the left non-hypertrophied hypoxic ventricle.
 ...
PMID:Induction of cardiac nitric oxide synthase 2 in rats exposed to chronic hypoxia. 1047 53

Endostatin is a 20 kDa carboxyl-terminal fragment of collagen XVIII that, when added exogenously, inhibits endothelial proliferation and migration in vitro and angiogenesis and tumor growth in vivo. Previous results showed endostatin/collagen XVIII labeling in few endothelial cells in human glioblastoma multiforme. We have now observed constitutive release of endostatin from one of four endothelial cell lines. Induction of endostatin release was observed after H2O2, an in vitro model of cell stress, CoCl2, a model of hypoxia, and by IFN-gamma challenge. Endostatin expression and release was reduced by the nitric oxide synthase inhibitors aminoguanidine and L-NAME and induced by the NO synthase-independent NO donors sodium nitroprusside (SNP) and spermine-NONO-ate. SNP-mediated endostatin induction was abrogated by the soluble guanylate cyclase inhibitor 1H-(1.2.4) oxadiazolo (4,3-A) quinoxalin-1-one. Adenoviral endostatin transduction resulted in the release of endostatin from endothelial cells and in down-regulation of iNOS (NOS2) and eNOS (NOS3), and surprisingly in a 10% induction of PCNA. These results describe the modulation of endostatin release by the NO signaling cascade and provide important new pharmacological information for the systemic induction of endogenous endostatin release by common NO donor pharmacotherapy.
 ...
PMID:Endothelial endostatin release is induced by general cell stress and modulated by the nitric oxide/cGMP pathway. 1283 91

Animal studies have suggested that nitric oxide (NO) synthases (NOS) play a role in the regulation of protein metabolism in endotoxemia. We therefore investigated the role of inducible NOS (NOS2) on intestinal protein and neuronal NOS (NOS1) and endothelial NOS (NOS3) on amino acid metabolism. Three groups of mice were studied: 1) wild-type (WT), 2) NOS2 knockout (NOS2-KO), and 3) NOS2-KO + N(omega)-nitro-l-arginine methyl ester (NOS2-KO + l-NAME), both in nonstimulated and LPS-treated conditions. By infusion of the stable isotopes l-[phenyl-(2)H(5)]Phe, l-[phenyl-(2)H(2)]Tyr, l-[guanidino-(15)N(2)]Arg, and l-[ureido-(13)C; (2)H(2)]citrulline (Cit), intestinal protein, amino acid, and Arg/NO metabolism were studied on the whole body level and across intestine. In nonstimulated situations, NOS2 deficiency increased whole body protein turnover and intestinal Gln uptake and Cit production. In NOS2-KO + l-NAME, the above-mentioned changes were reversed. After LPS in WT, whole body NO and Cit production increased. In contrast to this, LPS decreased net intestinal Gln uptake, whole body NO, and Cit production in NOS2-KO mice. Treatment of NOS2-KO + l-NAME with LPS was lethal in eight of eleven mice (73%). The surviving mice in this group showed a major drop in intestinal protein breakdown and synthesis to almost zero. Thus both in baseline conditions and during endotoxemia, the absence of NOS2 upregulated NOS1 and/or NOS3, which increased intestinal metabolism. The drop in intestinal protein metabolism in the endotoxemic NOS2-KO + l-NAME group might play a role in mortality in that group.
 ...
PMID:NOS2 deficiency increases intestinal metabolism both in nonstimulated and endotoxemic mice. 1465 12

An increased expression and activity of the heme oxygenase-1 (HO-1) in the liver has been observed in models of hepatic damage. Nitric oxide (NO) seems to be involved in HO-1 regulation. The aim of this work is to assess HO-1 induction and heme oxygenase (HO) activity in rats with bile duct ligation (BDL). We have assessed the effect of chronic inhibition of the NO synthesis by N(G)-nitro-l-arginine methyl ester (l-NAME) on HO-1 induction and HO activity. In the BDL animals, compared with sham-operated ones, we found an increased plasma nitrite and bilirubin concentration, and a marked liver expression of inducible nitric oxide synthase and HO-1, assessed by both Western blot and immunohistochemistry. Chronic l-NAME treatment prevented plasma nitrite increase in animals subjected to BDL. BDL animals treated with l-NAME, compared with untreated BDL rats, showed an important decrease in HO-1 expression and in HO activity (assessed as a decreased plasma bilirubin and bilirubin excretion). In conclusion, our experiments show parallel changes in expression and activity of HO-1 and NOS2 activity in the BDL model of liver damage and suggest that increased NO production is involved in HO-1 overexpression.
 ...
PMID:Relationships between NOS2 and HO-1 in liver of rats with chronic bile duct ligation. 1590 18

In the present study we investigated the lymphocytes infiltration and other parameters of allergic lung inflammation comparing mice submitted to acute suppression of nitric oxide synthesis with mice deficient in inducible nitric oxide synthase (NOS2-/-) gene. At weekly intervals C57Bl/6 mice, wild type and NOS2-/- were sensitized twice with ovalbumin-alumen and challenged twice with ovalbumin aerosol and lungs examined 24 h later. In wild type mice, treatment with nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine-methyl-ester (L-NAME) or aminoguanidine (i.p., 30 min before each ovalbumin challenge) caused a significant decrease in bronchoalveolar lavage cell number: eosinophils (90%), lymphocytes NK1.1+ (70%), Tgammadelta+ (50%), CD4+ (55%), CD8+ (60%) and B220+ (65%). Both inhibitors abolished airway hyperreactivity and significantly reduced mucus secretion (L-NAME 64%; aminoguanidine 58%). Surprisingly, in NOS2-/- mice these parameters of allergic lung inflammation were not significantly different when compared with wild type mice. In addition, treatment of NOS2-/- mice with L-NAME or aminoguanidine did not affect these parameters. Thus, acute inhibition of NOS2 activity inhibits asthma-like responses but absence of NOS2 has no affect.
 ...
PMID:Acute inhibition of inducible nitric oxide synthase but not its absence suppresses asthma-like responses. 1602 34

In experimental models of asthma, nitric oxide (NO) is produced and contributes to the physiopathology of the disease. Neutrophil is the first cell to infiltrate the lung in response to antigen stimulation, it has the capacity to produce NO but a clear demonstration that neutrophils contribute to NO production in asthma is lacking. This was the aim of the present study. At weekly intervals C57Bl/6 mice were sensitized twice with ovalbumin-alumen and challenged twice with ovalbumin aerosol. The peak of neutrophil infiltration in the bronchoalveolar lavage fluid (BALF) was 12 h after challenge, when neutrophils constituted 70% of the cell population and eosinophils only 1.5%. BALF cell preparations were stained with a NO-sensitive fluorescent dye (DAF-2) and with a nucleus marker (DAPI). Most DAF-2 stained cells could be identified as polymorphonuclear leukocytes, by the co-localization of both DAF-2 and DAPI staining. Cells from animals treated with l-NAME, were not stained for DAF-2 confirming the specificity of DAF-2 staining for NO. Moreover, the peak expression of inducible nitric oxide synthase (NOS2), in BALF cells and lung homogenates, was coincident with the peak of BALF neutrophil influx. NOS2 protein expression (arbitrary units) was detected 6 h after challenge (17.8+/-9.1 in BALF cells; 47.5+/-7.7 in lung homogenates), peak expression was at 12 h (54.5+/-8.7 and 133.7+/-10), decreasing thereafter, being no longer detected after 24 h. Thus, the neutrophils infiltrating the lung in the initial phase of murine asthma are producing NO via NOS2.
 ...
PMID:Production of nitric oxide by airways neutrophils in the initial phase of murine asthma. 1716 22

The uterine vasculature plays an important role during pregnancy by providing adequate perfusion of the maternal-fetal interface. To this end, substantial remodeling of the uterine vasculature occurs with consequent changes in responsiveness to contractile agents. The purpose of our study was to characterize the vasorelaxant effects of estrogens on vascular smooth muscles of the rat uterine artery during pregnancy and to evaluate the involvement of estrogen receptors (ESR) and nitric oxide synthases (NOS). To do so, we measured NOS expression in the whole uterine and mesenteric circulatory bed by Western blotting. Vasorelaxant effects of 17beta-estradiol (17beta-E(2)) were assessed on endothelium-denuded uterine arteries with wire myographs in the absence and presence of pharmacological modulators [nitro-L-arginine methyl ester (L-NAME), ICI-182780, tamoxifen]. All experiments were performed on arteries from nonpregnant (NP) and late pregnant (P) rats. In the uterine vasculature of the latter group, NOS3 (endothelial NOS) expression was increased, while NOS1 (neuronal NOS) was reduced compared with NP rats. Expression of the NOS2 (inducible NOS) isoform was undetectable in the two groups. Both 17beta-E(2) and 17alpha-E(2) induced uterine artery relaxation, but the latter evoked lower responses. Endothelium-denuded arteries from NP rats showed larger relaxation with 17beta-E(2) than P rats. This larger relaxation disappeared in the presence of L-NAME. The ESR antagonist ICI-182780 did not affect acute relaxation with 17beta-E(2) and 17alpha-E(2). Moreover, membrane-nonpermeant 17beta-E(2):BSA (estradiol conjugated to bovine serum albumin) did not induce any vasorelaxation. Our results indicate that estrogens exert direct acute vasorelaxant effects in smooth muscles of the rat uterine artery that are mediated by mechanisms independent of ESR activation, but with some stereospecificity. Part of this effect, in NP rats only, is due to nitric oxide produced from muscle NOS1.
 ...
PMID:Vasorelaxant action of 17 -estradiol in rat uterine arteries: role of nitric oxide synthases and estrogen receptors. 1795 67

Nitroalkene derivatives of fatty acids act as adaptive, anti-inflammatory signalling mediators, based on their high-affinity PPARgamma (peroxisome-proliferator-activated receptor gamma) ligand activity and electrophilic reactivity with proteins, including transcription factors. Although free or esterified lipid nitroalkene derivatives have been detected in human plasma and urine, their generation by inflammatory stimuli has not been reported. In the present study, we show increased nitration of cholesteryl-linoleate by activated murine J774.1 macrophages, yielding the mononitrated nitroalkene CLNO2 (cholesteryl-nitrolinoleate). CLNO2 levels were found to increase approximately 20-fold 24 h after macrophage activation with Escherichia coli lipopolysaccharide plus interferon-gamma; this response was concurrent with an increase in the expression of NOS2 (inducible nitric oxide synthase) and was inhibited by the (*)NO (nitric oxide) inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester). Macrophage (J774.1 and bone-marrow-derived cells) inflammatory responses were suppressed when activated in the presence of CLNO2 or LNO2 (nitrolinoleate). This included: (i) inhibition of NOS2 expression and cytokine secretion through PPARgamma and *NO-independent mechanisms; (ii) induction of haem oxygenase-1 expression; and (iii) inhibition of NF-kappaB (nuclear factor kappaB) activation. Overall, these results suggest that lipid nitration occurs as part of the response of macrophages to inflammatory stimuli involving NOS2 induction and that these by-products of nitro-oxidative reactions may act as novel adaptive down-regulators of inflammatory responses.
 ...
PMID:Macrophage activation induces formation of the anti-inflammatory lipid cholesteryl-nitrolinoleate. 1867 72


1 2 3 Next >>