Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We aimed to elucidate the possible role of phenotypic alterations and oxidative stress in age-related endothelial dysfunction of coronary arterioles. Arterioles were isolated from the hearts of young adult (Y, 14 weeks) and aged (A, 80 weeks) male Sprague-Dawley rats. For videomicroscopy, pressure-induced tone of Y and A arterioles and their passive diameter did not differ significantly. In A, arterioles L-NAME (a NO synthase blocker)-sensitive flow-induced dilations were significantly impaired (Y: 41+/-8% versus A: 3+/-2%), which could be augmented by superoxide dismutase (SOD) or Tiron (but not L-arginine or the TXA(2) receptor antagonist SQ29,548). For lucigenin chemiluminescence, O(2)(.-) generation was significantly greater in A than Y vessels and could be inhibited with SOD and diphenyliodonium. NADH-driven O(2)(.-) generation was also greater in A vessels. Both endothelial and smooth muscle cells of A vessels produced O(2)(.-) (shown with ethidium bromide fluorescence). For Western blotting, expression of eNOS and COX-1 was decreased in A compared with Y arterioles, whereas expressions of COX-2, Cu/Zn-SOD, Mn-SOD, xanthine oxidase, and the NAD(P)H oxidase subunits p47(phox), p67(phox), Mox-1, and p22(phox) did not differ. Aged arterioles showed an increased expression of iNOS, confined to the endothelium. Decreased eNOS mRNA and increased iNOS mRNA expression in A vessels was shown by quantitative RT-PCR. In vivo formation of peroxynitrite was evidenced by Western blotting, and immunohistochemistry showing increased 3-nitrotyrosine content in A vessels. Thus, aging induces changes in the phenotype of coronary arterioles that could contribute to the development of oxidative stress, which impairs NO-mediated dilations.
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PMID:Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. 1206 18

1. In the present study, endothelium-derived relaxing factor (EDRF/nitric oxide (NO)), conversion of big endothelin (ET)-1 to endothelin-1 (ET-1) and the role of reactive oxygen species were investigated in kidneys isolated from glycerol (GLY)-pretreated rabbits. 2. Acetylcholine (ACh)-induced vasodilation that is due to the release of EDRF/NO is significantly decreased, whereas big ET-1-induced vasoconstriction was increased in kidneys isolated from GLY-pretreated rabbits. 3. Pretreatment of rabbits with the xanthine oxidase inhibitor allopurinol and the NO precursor L-arginine reversed the inhibition of ACh-induced vasodilation due to GLY and protects the kidney vasculature. 4. Big ET-1, but not ET-1, responses were found to be significantly increased in kidneys isolated from GLY-pretreated rabbits. This increase is attributed to the higher conversion rate of big ET-1 to ET-1 because the ET-converting enzyme (ECE) inhibitor phosphoramidon, at a concentration of 10(-6) mol/L, causes an inhibition in the response to big ET-1 by 52.6% in normal kidneys, whereas this inhibition with the same concentration of phosphoramidon was found to be significantly decreased in kidneys isolated from GLY-pretreated rabbits. 5. The non-selective NO synthase inhibitor N(G)-nitro-L- arginine methyl ester (L-NAME) caused a significant potentiation in the vasoconstrictor response to ET-1 in normal isolated perfused rabbit kidneys. However, L-NAME did not alter the responses to ET-1 in GLY-pretreated kidneys. 6. These results indicate that accumulation of reactive oxygen species causes an inhibition in NO bioavailability. Increased conversion of big ET-1 to ET-1 may also contribute to the mechanism of vascular damage due to GLY.
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PMID:Effect of glycerol on endothelium-derived factors in the vasculature of the rabbit kidney. 1209 99

Free radicals have been implicated in the etiology of cardiac dysfunction during sepsis, but the actual species responsible remains unclear. We studied the alterations in myocardial nitric oxide (NO), superoxide, and peroxynitrite generation along with cardiac mechanical function and efficiency in hearts from lipopolysaccharide (LPS)-treated rats. Six hours after LPS (4 mg/kg ip) or saline (control) treatment, hearts were isolated and perfused for 1 h with recirculating Krebs-Henseleit buffer and paced at 300 beats/min. Cardiac work, O(2) consumption, and cardiac efficiency were markedly depressed in LPS hearts compared with controls. Plasma nitrate/nitrite level was elevated in LPS rats, and ventricular NO production was enhanced as measured by electron spin resonance spectroscopy, Ca(2+)-independent NO synthase (NOS) activity, and inducible NOS immunohistochemistry. Ventricular superoxide production was also enhanced in LPS-treated hearts as seen by lucigenin chemiluminescence and xanthine oxidase activity. Increased nitrotyrosine staining (immunohistochemistry) and higher lipid hydroperoxides levels were also detected in LPS-treated hearts, indicating oxygen radical-induced stress. Enhanced generation of both NO and superoxide, and thus peroxynitrite, occur in dysfunctional hearts from endotoxemic rats.
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PMID:Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. 1218 Nov 41

Besides NO, neuronal NO synthase (nNOS) also produces superoxide (O(2)(-.) at low levels of L-arginine. Recently, heat shock protein 90 (hsp90) was shown to facilitate NO synthesis from eNOS and nNOS. However, the effect of hsp90 on the O(2)(-.) generation from NOS has not been determined yet. The interrelationship between its effects on O(2)(-.) and NO generation from NOS is also unclear. Therefore, we performed electron paramagnetic resonance measurements of O(2)(-.) generation from nNOS to study the effect of hsp90. Purified rat nNOS generated strong O(2)(-.) signals in the absence of L-arginine. In contrast to its effect on NO synthesis, hsp90 dose-dependently inhibited O(2)(-.) generation from nNOS with an IC(50) of 658 nM. This inhibition was not due to O(2)(-.) scavenging because hsp90 did not affect the O(2)(-.) generated by xanthine oxidase. At lower levels of L-arginine where marked O(2)(-.) generation occurred, hsp90 caused a more dramatic enhancement of NO synthesis from nNOS as compared to that under normal L-arginine. Significant O(2)(-.) production was detected from nNOS even at intracellular levels of L-arginine. Adding hsp90 prevented this O(2)(-.) production, leading to enhanced nNOS activity. Thus, these results demonstrated that hsp90 directly inhibited O(2)(-.) generation from nNOS. Inhibition of O(2)(-.) generation may be an important mechanism by which hsp90 enhances NO synthesis from NOS.
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PMID:Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation. 1218 46

Treatment of carcinoma cell lines with 15-deoxy-delta12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-gamma, has been reported to induce apoptosis and/or inhibit proliferation. In this study, we investigated the cytotoxic effect and the action mechanisms of 15d-PGJ2 in a thyroid papillary cancer cell line, CG3. The results indicate that 15d-PGJ2 caused cytotoxicity and increased the amount of intracellular reactive oxygen species (ROS) in these cells. Mitochondrial oxidative phosphorylation inhibitors (carbonyl cyanide m-chloro-phenylhydrazone, oligomycin, cyclosporin A and rotenone), NADPH oxidase inhibitor (diphenyleneiodonium), xanthine oxidase inhibitor (allopurinol) and NO synthase inhibitor (N-monomethyl-L-arginine acetate) did not reduce the generation of ROS. However, catalase, N-acetyl-cysteine and the iron chelator desferri-oxamine decreased the intracellular ROS of 15d-PGJ2-treated CG3 cells. Furthermore, 15d-PGJ2 enhanced the accumulation of iron in the CG3 cells. These data suggest that 15d-PGJ2 induces the generation of ROS by enhancing the accumulation of intracellular iron and that the increased oxidative stress may cause apoptosis of CG3 cells.
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PMID:15-Deoxy-delta12,14-prostaglandin J2 induces apoptosis of a thyroid papillary cancer cell line (CG3 cells) through increasing intracellular iron and oxidative stress. 1218 33

The chemical origins of nitrated tyrosine residues (NT) formed in proteins during a variety of pathophysiological conditions remain controversial. Although numerous studies have concluded that NT is a signature for peroxynitrite (ONOO(-)) formation, other works suggest the primary involvement of peroxidases. Because metal homeostasis is often disrupted in conditions bearing NT, the role of metals as catalysts for protein nitration was examined. Cogeneration of nitric oxide (NO) and superoxide (O(2)(-)), from spermine/NO (2.7 microM/min) and xanthine oxidase (1-28 microM O(2)(-)/min), respectively, resulted in protein nitration only when these species were produced at approximately equivalent rates. Addition of ferriprotoporphyrin IX (hemin) to this system increased nitration over a broad range of O(2)(-) concentrations with respect to NO. Nitration in the presence of superoxide dismutase but not catalase suggested that ONOO(-) might not be obligatory to this process. Hemin-mediated NT formation required only the presence of NO(2)(-) and H(2)O(2), which are stable end-products of NO and O(2)(-) degradation. Ferrous, ferric, and cupric ions were also effective catalysts, indicating that nitration is mediated by species capable of Fenton-type chemistry. Although ONOO(-) can nitrate proteins, there are severe spatial and temporal constraints on this reaction. In contrast, accumulation of metals and NO(2)(-) subsequent to NO synthase activity can result in far less discriminate nitration in the presence of an H(2)O(2) source. Metal catalyzed nitration may account for the observed specificity of protein nitration seen under pathological conditions, suggesting a major role for translocated metals and the labilization of heme in NT formation.
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PMID:Protein nitration is mediated by heme and free metals through Fenton-type chemistry: an alternative to the NO/O2- reaction. 1222 78

There is great evidence in recent years that oxygen free radicals play an important role in the pathophysiology of schizophrenia. The present study was performed to assess the changes in plasma nitric oxide (NO) and thiobarbituric acid-reactive substances (TBARS) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and xanthine oxidase (XO) activities in schizophrenic patients compared to age- and sex-matched normal controls. A hundred patients with schizophrenia and 51 healthy volunteers were included in the study. XO, SOD, and GSH-Px activities as well as NO and TBARS levels were estimated by standard biochemical techniques in the plasma of normal healthy controls and schizophrenia patients. In schizophrenia, increased plasma XO activity (P < .0001) and NO levels (P < .0001), decreased SOD activity (P < .0001), and unchanged GSH-Px activity were detected compared to control group. Plasma TBARS levels were increased in schizophrenic patients (P < .01), especially in the residual subtype. TBARS levels in nonsmoker schizophrenic patients were found to be higher than nonsmoker controls. Although TBARS levels in both patients and controls were found to be higher in smokers as compared to nonsmokers, it was not statistically significant. No effects of duration of the illness, gender, and low and high dose of daily neuroleptic treatment equivalent to chlorpromazine on oxidant and antioxidant parameters were observed. Because the dose and the duration of treatment with drugs have no influence on the results, it can be interpreted that the findings are more likely to be related mainly to the underlying disease. These findings indicated a possible role of increased oxidative stress and diminished enzymatic antioxidants, both of which may be relevant to the pathophysiology of schizophrenia. On the other hand, increased NO production by nitric oxide synthetases (NOSs) suggests a possible role of NO in the pathophysiological process of schizophrenia. These findings may also suggest some clues for the new treatment strategies with antioxidants and NO synthase (NOS) inhibitors in schizophrenia.
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PMID:The indices of endogenous oxidative and antioxidative processes in plasma from schizophrenic patients. The possible role of oxidant/antioxidant imbalance. 1236 76

Nitric oxide degradation linked to endothelial dysfunction plays a central role in cardiovascular diseases. Superoxide producing enzymes such as NADPH oxidase and xanthine oxidase are responsible for NO degradation as they generate a variety of reactive oxygen species (ROS). Moreover, superoxide is rapidly degraded by superoxide dismutase to produce hydrogen peroxide leading to the uncoupling of NO synthase and production of increased amount of superoxide. Angiotensin II is an important stimulus of NADPH oxidase. Through its AT(1) receptor, Ang II stimulates the long-term increase of several membrane component of NADPH oxidase such as P(22) phox or nox-1 and causes an increased activity of NADPH oxidase with inactivation of NO leading to impaired endothelium-dependent vasorelaxation, vascular smooth muscle cell hypertrophy, proliferation and migration, extracellular matrix formation, thrombosis, cellular infiltration and inflammatory reaction. Several preclinical and clinical studies have now confirmed the involvement of the AT(1) receptor in endothelial dysfunction. It is proposed that the AT(2) receptor counterbalances the deleterious effect of the Ang II-induced AT(1) receptor stimulation through bradykinin and NOS stimulation. This mechanism could be especially relevant in pathological cases when the NADPH oxidase activity is blocked with an AT(1) receptor antagonist.
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PMID:Angiotensin II and nitric oxide interaction. 1237 20

Among components of oxidized low density lipoproteins, cholesterol derivatives oxidized in position 7 inhibit endothelium-dependent arterial relaxation by decreasing the release of the main endothelium-derived relaxing factor, nitric oxide (NO). The aim of the present study was to bring new insights into the molecular mechanism by which 7-ketocholesterol can block the endothelium-dependent arterial relaxation. Superoxide dismutase did not prevent the inhibitory effect of 7-ketocholesterol on endothelium-dependent relaxation, and consistent observations were made whether superoxide dismutase was conjugated or not to polyethylene glycol. In addition, neither glutathione supplementation, nor oxypurinol, i.e. a xanthine oxidase inhibitor could reverse the effect of 7-ketocholesterol, indicating that NO was not inactivated by superoxide anion. A direct alteration of the activity of the calcium-dependent NO synthase could also be ruled out, since identical relaxing effects of the calcium ionophore A23187 were observed whether arterial rings were treated or not with 7-ketocholesterol. 4 Whereas the above observations come in support of an early, inhibitory action of 7-ketocholesterol, the specific blockade of one given subtype of membrane receptors could be discarded, and similar inhibitions were observed when either muscarinic or purinergic receptors were stimulated. Finally, the blockade of protein kinase C activity by chelerythrine arose as the sole relevant tool in preventing the effect of 7-ketocholesterol on the endothelium-dependent relaxation of rabbit aortic rings. In addition, complementary studies on cultured bovine aortic endothelial cells came in direct support of the ability of 7-ketocholesterol to activate PKC. In conclusion, 7-ketocholesterol that is present in human hypercholesterolaemic plasma, in atherosclerotic arteries, and in many processed foods can block the release of NO by vascular endothelial cells through its ability to activate PKC.
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PMID:The impairment of endothelium-dependent arterial relaxation by 7-ketocholesterol is associated with an early activation of protein kinase C. 1238 79

We tested the hypothesis that ceramide induces endothelial dysfunction in small coronary arteries via NADPH oxidase-mediated superoxide and resulting peroxynitrite formation. With the use of dihydroethidium as a superoxide indicator, C(2)-ceramide was found to increase superoxide production in the endothelial cells of small coronary arteries, which was inhibited by the NADPH oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium. NADPH oxidase expression was confirmed in endothelial cells, as indicated by the immunoblotting of its subunits gp91(phox) and p47(phox). C(2)-ceramide increased NADPH oxidase activity by 52%, which was blocked by NADPH oxidase inhibitors but not by inhibitors of NO synthase, xanthine oxidase, and mitochondrial electron transport chain enzymes. By Western blot analysis, ceramide-induced NADPH oxidase activation was found to be associated with the translocation of p47(phox) to the membrane. In isolated and pressurized small coronary arteries, N-vanillylnonanamide, apocynin, or uric acid, a peroxynitrite scavenger, largely restored the inhibitory effects of ceramide on bradykinin- and A-23187-induced vasorelaxation. With the use of nitrotyrosine as a marker, C(2)-ceramide was found to increase peroxynitrite in small coronary arteries, which could be blocked by uric acid. We conclude that NADPH oxidase-mediated superoxide production and subsequent peroxynitrite formation mediate ceramide-induced endothelial dysfunction in small coronary arteries.
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PMID:Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small coronary arteries. 1242 96


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