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

The synthesis of thromboxane B2 is increased in platelets from rabbits with experimental hypercholesterolemia, but the increase is not due to increased phospholipids hydrolysis. We have clarified the mechanism for the increased thromboxane synthesis. The biosyntheses of prostaglandin H2 and thromboxane B2 were unaffected by superoxide dismutase, xanthine oxidase, mannitol, or benzoate in other experiments designed to study the possible involvement of reactive oxygen species. These results suggest that O2.- and OH were not likely to be involved as intermediates in the synthesis of prostaglandin H2 and thromboxane B2 in platelets. The rate of prostaglandin H2 biosynthesis was promoted in deuterium oxide, and this deuterium oxide enhancement effect was reversed by 2,5-diphenylfuran, suggesting that singlet oxygen may be involved in prostaglandin H2 biosynthesis. The biosynthesis of prostaglandin H2 was promoted by ADP-Fe3+ but inhibited by EDTA and EDTA-Fe3+. The effect of ADP-Fe3+ could not be replaced by EDTA-Fe3+. The effects of glutathione, glutathione peroxidase and H2O2 on cyclooxygenase and thromboxane synthetase were studied by using partially purified enzymes and platelet microsomes. Glutathione and glutathione peroxidase inhibited the activity of cyclooxygenase but did not inhibit that of thromboxane synthetase. H2O2 caused the inactivation of cyclooxygenase, but the addition of H2O2 did not inhibit the formation of thromboxane B2 from prostaglandin H2. An examination of glutathione concentration and glutathione peroxidase activity in platelets from normal and experimentally hypercholesterolemic rabbits demonstrated that both were decreased in platelets from later group. The observed alterations in glutathione levels and glutathione peroxidase activity are large enough to cause increased thromboxane B2 synthesis in platelets but the possibility that other unidentified factors may also contribute cannot be excluded.
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PMID:Increased thromboxane B2 biosynthesis in platelets. 681 1

Production/release of superoxide anions from aortic rings was measured by a modified lucigenin-enhanced chemiluminescence (CL) technique. The aortic rings were obtained from control and cholesterol-fed (1% for 12 weeks) rabbits. The CL signal was significantly increased in aortic wall of cholesterol-fed rabbits. Pretreatment with oxypurinol, an inhibitor of xanthine oxidase, had a slight but insignificant effect on the CL response produced by aortic rings from control animals but significantly reduced CL response to aortic rings from cholesterol-fed rabbits. Pretreatment with diethyldithiocarbamate (DETC), an inhibitor of intrinsic superoxide dismutase (SOD), increased the CL signal for both animal groups, but this increase was greatly aggravated in aortic rings from hypercholesterolemic rabbits. Addition of phorbol 12-myristate 13 acetate (PMA) to stimulate the respiratory burst of wall-adherent and/or resident leukocytes had only slight effect on the CL response to aortic rings from control animals but extensively stimulated photon emission of aortic rings from cholesterol-fed rabbits. These findings are in agreement with the concept that the arterial wall in hypercholesterolemia and/or atherosclerosis is under increased "oxidative stress."
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PMID:Vascular release of superoxide radicals is enhanced in hypercholesterolemic rabbits. 789 85

Indirect evidence suggests accelerated degradation of endothelium-derived nitric oxide (ENDO) by superoxide anion (O2-) in hypercholesterolemic vessels (HV). To directly measure O2- production by normal vessels (NV) and HV, we used an assay for O2- based on the chemiluminescence (CL) of lucigenin (L). HV (1 mo cholesterol-fed rabbits) produced threefold more O2- than NV (1.47 +/- 0.20 nM/mg tissue/min, n = 7 vs. 0.52 +/- 0.05 nmol/mg tissue/min, n = 8, P < 0.001). Endothelial removal increased O2- production in NV (0.73 +/- 0.08, n = 6, P < 0.05), while decreasing it in HV (0.76 +/- 0.15, n = 5, P < 0.05). There was no difference between denuded HV and denuded NV. Oxypurinol, a noncompetitive inhibitor of xanthine oxidase, normalized O2- production in HV, but had no effect in NV. In separate isometric tension studies treatment with oxypurinol improved acetylcholine induced relaxations in HV, while having no effect on responses in normal vessels. Oxypurinol did not alter relaxations to nitroprusside. Thus, the endothelium is a source of O2- in hypercholesterolemia probably via xanthine oxidase activation. Increased endothelial O2- production in HV may inactivate endothelium-derived nitric oxide and provide a source for other oxygen radicals, contributing to the early atherosclerotic process.
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PMID:Hypercholesterolemia increases endothelial superoxide anion production. 839 Apr 82

In several species, xanthine oxidoreductase activity seems to be a major source of free radicals in myocardial tissue. Its activity changes during development and aging, at least in the rat heart. Hardly any data are available about its activity in two important diseases, hypertension and hypercholesterolemia, in which the production of free radicals induced by xanthine oxidoreductase activity could play a role. Therefore we measured the activity of xanthine oxidase and dehydrogenase in myocardial tissue of spontaneously hypertensive. Wistar (control hypertensive), Yoshida (hypercholesterolemic) and Brown Norway (control hypercholesterolemic) rats of various ages. Cytosolic fractions were incubated at 30 degrees C, pH 8.3, with 60 microM xanthine, and the formation of urate was measured with high performance liquid chromatography. In the Wistar group, xanthine oxidoreductase activity was relatively constant during aging (about 1.8 U/g protein). In the hypertensive group, the activity increased gradually from 1.7 to 2.3 U/g at 18 months (p < 0.05 compared with Wistar at 18 months). Xanthine oxidase was about twice as high in both groups at 18 months (p < 0.001 compared with 2 and 6 months). The ratio of xanthine dehydrogenase to xanthine oxidase had decreased 42% at this age (p < 0.001). In the Yoshida and Brown Norway groups, xanthine oxidoreductase activity was similar, with a peak at 6 months. These data suggest that the hypercholesterolemic state does not influence xanthine oxidoreductase activity. In contrast, in hypertrophied myocardium, xanthine oxidoreductase activity was higher than in the control, suggesting a different potential for free-radical generation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial xanthine oxidoreductase activity in hypertensive and hypercholesterolemic rats. 847 39

Although the involvement of free radicals in the development of endothelial dysfunction under pathological conditions, like diabetes and hypercholesterolemia, has been proposed frequently, there is limited knowledge as to how superoxide anions (O2-) might affect endothelial signal transduction. In this study, we investigated the effects of preincubation with the O2(-)-generating system xanthine oxidase/hypoxanthine (XO/HX) on mechanisms for Ca2+ signaling in cultured porcine aortic endothelial cells. Incubation of cells with XO/HX yielded increased intracellular Ca2+ release and capacitative Ca2+ entry in response to bradykinin and ATP in a time- and concentration-dependent manner. This effect was prevented by superoxide dismutase but not by the tyrosine kinase inhibitor tyrphostin A48. In addition, capacitative Ca2+ entry induced by the receptor-independent stimulus 2,5-di-(tert-butyl)-1,4-benzohydroquinone or thapsigargin was enhanced in O2(-)-exposed cells (+38% and +32%, respectively). Increased Ca2+ release in response to bradykinin in XO/HX-pretreated cells might be due to enhanced formation of inositol-1,4,5-trisphosphate (+140%). Exposure to XO/HX also affected other signal transduction mechanisms involved in endothelial Ca2+ signaling, such as microsomal cytochrome P450 epoxygenase and membrane hyperpolarization to Ca2+ store depletion with thapsigargin (+103% and +48%, respectively) and tyrosine kinase activity (+97%). A comparison of bradykinin-initiated intracellular Ca2+ release and thapsigargin-induced hyperpolarization with membrane viscosity modulated by XO/HX (decrease in viscosity) or cholesterol (increase in viscosity) reflected a negative correlation between bradykinin-initiated Ca2+ release and membrane viscosity. Because intracellular Ca2+ is a main regulator of endothelial vascular function, our data suggest that O2- anions are involved in regulation of the vascular endothelium.
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PMID:Effects of superoxide anions on endothelial Ca2+ signaling pathways. 974 37

Synthesis of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) is critical for normal vascular homeostasis. eNOS function is rapidly regulated by agonists and blood flow and chronically by factors that regulate mRNA stability and gene transcription. Recently, localization of eNOS to specialized plasma membrane invaginations termed caveolae has been proposed to be required for maximal eNOS activity. Because caveolae are highly enriched in cholesterol, and hypercholesterolemia is associated with increased NO production, we first studied the effects of cholesterol loading on eNOS localization and NO production in cultured bovine aortic endothelial cells (BAECs). Caveolae-enriched fractions were prepared by OptiPrep gradient density centrifugation. Treatment of BAECs with 30 microgram/mL cholesterol for 24 hours stimulated significant increases in total eNOS protein expression (1.50-fold), eNOS associated with caveolae-enriched membranes (2.23-fold), and calcium ionophore-stimulated NO production (1.56-fold). Because reactive oxygen species (ROS) contribute to endothelial dysfunction in hypercholesterolemia, we next studied the effects of ROS on eNOS localization and caveolae number. Treatment of BAECs for 24 hours with 1 micromol/L LY83583, a superoxide-generating napthoquinolinedione, decreased caveolae number measured by electron microscopy and prevented the cholesterol-mediated increases in eNOS expression. In vitro exposure of caveolae-enriched membranes to ROS (xanthine plus xanthine oxidase) dissociated caveolin more readily than eNOS from the membranes. These results show that cholesterol treatment increases eNOS expression, whereas ROS treatment decreases eNOS expression and the association of eNOS with caveolin in caveolae-enriched membranes. Our data suggest that oxidative stress modulates endothelial function by regulating caveolae formation, eNOS expression, and eNOS-caveolin interactions.
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PMID:Opposing effects of reactive oxygen species and cholesterol on endothelial nitric oxide synthase and endothelial cell caveolae. 1040 Sep 8

1. Hypercholesterolaemia is associated with abnormal endothelium-related vasodilator function, possibly due to increased destruction .NO by superoxide anions (.O2-). Oxypurinol, a xanthine oxidase (XO) inhibitor with anti-oxidant properties and the active metabolite of the commonly used drug allopurinol, reduces .NO quenching in vitro and has been reported to acutely improve endothelial function in hypercholesterolaemic subjects. 2. The purpose of the present study was to determine whether oral allopurinol improves .NO dilator function in hypercholesterolaemic subjects. 3. A randomized double-blind, placebo-controlled cross-over design evaluated the effect of allopurinol (300 mg daily for 4 weeks) on forearm blood flow (FBF) responses to intrabrachial infusion of acetylcholine (ACh), sodium nitroprusside (SNP) and NG-monomethyl-L-arginine (L-NMMA) in nine hypercholesterolaemic subjects. 4. Endothelium-dependent vascular responses to ACh and L-NMMA were not significantly altered by allopurinol. The endothelium-independent vasodilator response to SNP was similarly unchanged. 5. These results indicate that allopurinol does not influence basal or stimulated activity of the .NO dilator system in hypercholesterolaemic subjects. If intracellular .O2- inactivation .NO is responsible for endothelial dysfunction in hypercholesterolaemia, the source may be other than XO dependent. However, generation of .O2- during the conversion of allopurinol to oxypurinol could offer an alternative, and probably more likely, explanation for the ineffectiveness of allopurinol in vivo.
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PMID:Nitric oxide-dependent endothelial function is unaffected by allopurinol in hypercholesterolaemic subjects. 1054 1

There is evidence that, besides an attenuated endothelium-dependent relaxation, functional changes in smooth muscle contractility occur in experimental hypercholesterolemic animals. Unfortunately, little is known of the situation in human arteries, and the intracellular mechanisms involved in the modulation of vascular smooth muscle function in human hypercholesterolemia are still unclear. Thus, besides acetylcholine-induced endothelium-dependent relaxation, smooth muscle reactivity to KCl, norepinephrine (NE) and phenylephrine (PE) was evaluated in uterine arteries from 34 control individuals (CI) and 22 hypercholesterolemic patients (HC). Contractions to KCl, norepinephrine and phenylephrine were enhanced by 1.3-, 2.1- and 3.5-fold in vessels from HC. Furthermore, the Ca(2+) signaling in the perinuclear cytosol, which promotes cell contraction, and that of the subplasmalemmal region, which contributes to smooth muscle relaxation, were examined in freshly isolated smooth muscle cells. In cells from HC, increases in perinuclear Ca(2+) concentration ([Ca(2+)](peri)) in response to 30 mM KCl and 300 nM NE were increased by 67 and 93%, respectively. In contrast, the increase in the subplasmalemmal Ca(2+) concentration ([Ca(2+)](sub)) to 10 microM NE was reduced in cells from HC by 33%. No further differences in perinuclear and subplasmalemmal Ca(2+) signaling were found in cultured smooth muscle cells from CI and HC (primary culture 4-6 weeks after isolation). These data indicate a significant change in the subcellular Ca(2+) distribution in smooth muscle cells from HC. In addition, production of superoxide anions (O(2)(-)) was increased 3.8-fold in uterine arteries from HC. Treatment of smooth muscle cells with the O(2)(-)-generating mixture xanthine oxidase/hypoxanthine mimicked hypercholesterolemia on smooth muscle Ca(2+) signaling. From these findings, we conclude that during hypercholesterolemia, besides a reduced endothelium-dependent relaxation, changes in smooth muscle reactivity take place. Thereby, smooth muscle contractility is increased possibly due to the observed changes in subcellular Ca(2+) signaling. The observed increased O(2)(-) production in HC might play a crucial role in the alteration of smooth muscle function in hypercholesterolemia.
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PMID:In human hypercholesterolemia increased reactivity of vascular smooth muscle cells is due to altered subcellular Ca(2+) distribution. 1070 12

In hypercholesterolemia in the presence or absence of atherosclerosis, cardiovascular dysfunction and altered signaling of angiotensin, nitric oxide, or prostanoids are closely related to enhanced oxidant stress. We analyzed the potentially beneficial effects of the specific angiotensin-converting enzyme inhibitor enalapril and the specific angiotensin receptor blocker losartan on cardiac performance, eicosanoid metabolism, and parameters of oxidant stress in hypercholesterolemic animals. Guinea pigs were fed a 1% cholesterol diet for 8 weeks (Chol) with or without equieffective doses of either enalapril (1.5 mg/kg/d; Ena) or losartan (3 mg/kg/d; Los). Hemodynamics were analyzed in Langendorff hearts. Detection of eicosanoids was by enzyme immunoassay. Estimation of plasma xanthine oxidase (XO) activity was determined by spectrophotometry. In hypercholesterolemic guinea pigs, enhanced oxidant stress (e.g., increased plasma XO activities) was associated with profound myocardial and coronary (e.g., endothelial) dysfunction. Both enalapril and losartan lowered plasma cholesterol levels slightly, but only the angiotensin receptor antagonist effectively suppressed the increased plasma XO activities (from 11.4 +/- 0.7 to 7.6 +/- 2.2 U/L), and at the same time decreased the augmented coronary flow (from 26.0 +/- 1.0 to 23.0 +/- 1.0 mL/min/g tissue) observed in hypercholesterolemic animals. Assessment of left ventricular pressure and contractility (e.g., dp/dtmax) as well as the diastolic relaxation parameter (tau) revealed substantial myocardial dysfunction (systolic and diastolic) in Chol that was more substantially (and comparably) improved during administration of losartan (Los) than during enalapril (Ena). Surprisingly, angiotensin signaling blockade by either antagonist further suppressed the diminished coronary dilator responses to bradykinin (BK; not significant for enalapril) or adenosine (Ado) was demonstrated in Chol Langendorff hearts [delta CPPBK/Ado: from 5.0 +/- 0.5/0.9 +/- 0.1 to 4.4 +/- 1.5/0.4 +/- 0.1 (Ena) or to 1.9 +/- 0.5/0.4 +/- 0.1 (Los) cm2 (area under the curve), respectively]. Finally, as expected from control studies using heart preparations from normocholesterolemic guinea pigs, enhanced cardiac release of eicosanoids, prostacyclin, and thromboxane in Chol (0.48 +/- 0.03 and 0.6 +/- 0.1 ng/min/g) was augmented even further by treatment with enalapril (Ena: 1.6 +/- 0.4 and 1.0 +/- 0.1 ng/min/g), but was significantly reduced to or below control levels in losartan-treated animals (Los: 0.4 +/- 0.1 and 0.2 +/- 0.1 ng/min/g). Blockade of angiotensin signaling via angiotensin-converting enzyme inhibition or receptor antagonism--although differentially acting on enhanced cardiac prostanoid metabolism and oxidant stress--efficiently restored proper systolic and diastolic myocardial performance (losartan was more beneficial than enalapril), probably by counterbalancing altered angiotensin II-->angiotensin receptor signaling in the cardiovascular system of hypercholesterolemic animals. Impaired coronary vasodilator capacity seems to be irreversible after 8 weeks of a high-cholesterol diet, as shown by the unexpected lack of a dilator effect with both enalapril and losartan.
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PMID:Blockade of angiotensin signaling improves myocardial function in hypercholesterolemia independent of changes in eicosanoid release. 1093 54

Accumulating evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO(.)) by superoxide and other reactive oxygen species (ROS) seems to occur in conditions such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking. Loss of NO(.) associated with these traditional risk factors may in part explain why they predispose to atherosclerosis. Among many enzymatic systems that are capable of producing ROS, xanthine oxidase, NADH/NADPH oxidase, and uncoupled endothelial nitric oxide synthase have been extensively studied in vascular cells. As the role of these various enzyme sources of ROS become clear, it will perhaps be possible to use more specific therapies to prevent their production and ultimately correct endothelial dysfunction.
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PMID:Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. 1107 78


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