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)

Cardiac ischemia is characterized by rapid deterioration of cardiac function, which has been linked to the fall in intracellular pH, increased levels of inorganic phosphate and reduction in free energy change of ATP-hydrolysis. Biochemical events responsible for irreversible myocardial injury involve various mechanisms which change the properties of the cardiac cell membrane (disorders in lipid metabolism, free radical formation). Recent evidence suggests that in the heart, xanthine oxidase is a major source of free radical formation. During ischemia, adenine-nucleotide breakdown in the cardiomyocyte proceeds only to the stage of inosine. Due to the localisation of nucleoside phosphorylase and xanthine-oxidase in vascular endothelium, further degradation of inosine to hypoxanthine, xanthine and uric acid occurs predominantly in the vascular space. It is therefore conceivable that the primary site of reperfusion injury in the ischemic heart may be the coronary endothelium damaged by free radicals.
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PMID:Mechanisms of ischemic injury in the heart. 390 19

The morphological, biochemical and functional characterization of the vascular endothelium has become possible through the broad use of electron microscopic methods, the successful elaboration and application of techniques for the isolation and cultivation of endothelial cells in vitro and through sophisticated studies on vessel and organ preparations, both in vitro and in vivo. In this survey emphasis is placed on certain methodological aspects of endothelial cell culture as well as on biochemical, physiological and pathophysiological features of the vascular endothelium. Endothelial cells can be propagated in culture dishes, the most commonly applied method, on suspended microbeads (dextrane, polyacrylamide), a technique giving large yields, or on thin porous membranes, a procedure suited for the study of transport processes across the endothelial layer. Different structural, biochemical and functional properties of the luminal (apical) and abluminal (basal) cell membrane determine important polarity features of the endothelium. Endothelial cells exhibit a variety of biochemical pathways and are characterized by high metabolic activities. Of particular interest is the large content of ATP in endothelial cells of different vascular origin. The rapid intracellular degradation of adenine nucleotides to nucleosides and bases, which are constantly released, is balanced by synthesis, mainly via salvage pathways. In endothelial cells of microvascular origin uric acid predominates by far as the final purine degradative because of the presence of xanthine dehydrogenase in these cells; in the macrovascular endothelium purine breakdown proceeds only to hypoxanthine, since xanthine dehydrogenase is lacking. In this connection interrelations between nucleotide catabolism in myocardial tissue and in coronary endothelial cells are discussed, also with respect to the participation of endothelial xanthine oxidase in the formation of oxygen radicals during post-ischemic reperfusion of the heart. Vascular endothelial cells of different origin are also capable of a rapid extracellular degradation of ATP, ADP and AMP to adenosine by means of specific ecto-nucleotidases. The subsequent fate of extracellularly formed adenosine appears to be different for endothelial cells of microvascular (preferential adenosine uptake) and macrovascular origin (preferential extracellular adenosine accumulation), thus implying functional consequences for platelet aggregation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The vascular endothelium: a survey of some newly evolving biochemical and physiological features. 393 1

Oxygen-derived free radicals have been proposed as general mediators of tissue injury in a variety of disease states. Recent interest has focused on the possibility that free radicals may be involved in ischemic myocardial damage. However, the exact types of damage that result from myocardial exposure to free radicals remains to be established. The purpose of this study was to evaluate the effects of superoxide and hydroxyl radicals on myocardial structure and function in an isolated perfused rabbit interventricular septal preparation. Superoxide was generated by adding purine (2.3 mM) and xanthine oxidase (0.01 U/ml) to the physiological solutions perfusing the septa. Hydroxyl radical generation was catalyzed by the addition of 2.4 microM Fe3+-loaded transferrin to the system. Exposure of normal septa to superoxide-generating solutions resulted in the development of structural alterations in the vascular endothelium including the development of vacuoles. Membranous cellular debris was evident in the extracellular space and within the vessels. Cardiac myocytes showed evidence of mild alterations. Exposure of septa to solutions capable of generating hydroxyl radicals resulted in more extensive and severe damage. Vascular endothelial cells showed evidence of vacuoles or blebs and edema. Severe swelling of mitochondria was evident in cardiac myocytes and vascular endothelial cells. In addition, myocytes often showed blebbing of the basement membrane. Normal septa exposed to superoxide showed no significant decrease in developed tension, whereas hydroxyl radical exposure resulted in a significant decrease in myocardial function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Myocardial alterations due to free-radical generation. 633 Nov 79

Reactive oxygen metabolites generated from xanthine oxidase play an important role in the pathogenesis of ischemia-induced tissue injury. In a hemorrhagic shock model of ischemia-reperfusion, the intracellular enzyme xanthine oxidase was released into the vasculature. This intravascular source of superoxide (O2.-) and hydrogen peroxide (H2O2) interacted reversibly with glycosaminoglycans of vascular endothelium and markedly concentrated xanthine oxidase at cell surfaces, enhancing its ability to produce extensive damage to remote tissues. Rats were made hypotensive by hemorrhage, maintained for 2h, and reinfused with shed blood. Blood samples were obtained prior to hemorrhage and 15, 30, 60, and 90 min after reperfusion for determination of xanthine oxidase (XO), lactate dehydrogenase (LDH), and alanine transaminase (AST). These enzymes were not significantly elevated in control animals. Reperfusion after hemorrhage-induced ischemia resulted in significantly elevated AST and LDH in both low heparin (100 U/h) and high heparin (1000 U/h) groups. Xanthine oxidase was detected in the circulation only after 90 min reperfusion in the low heparin group and was elevated during the entire reperfusion period in the high heparin group. Studies with cultured vascular endothelium showed significant heparin-reversible binding of XO to cellular glycosaminoglycans. These results suggest that XO can gain access to the circulation following ischemia, where it then binds to the vascular endothelial cells to produce site-specific oxidant injury to organs remote from the site of XO release.
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PMID:Xanthine oxidase activity in the circulation of rats following hemorrhagic shock. 822 22

Sodium tanshinone IIA sulfonate (STS) is a derivative of tanshinone IIA. The latter is a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza. Liquid chromatographically pure STS was found to reduce myocardial infarct size by 53.14 +/- 22.79% relative to that in the saline control in a rabbit 1 hr-ischemia and 3 hr-reperfusion model. This effect was comparable to that of Trolox (a better characterized antioxidant serving as a reference cytoprotector), which salvaged the myocardium in the same infarct model by 62.13 +/- 18.91%. Also, like Trolox, STS did not inhibit oxygen uptake by xanthine oxidase (XO), a key enzyme in free radical generation. However, in contrast to Trolox, STS significantly prolonged the survival of cultured human saphenous vein endothelial cells but not human ventricular myocytes in vitro when these cells were separately exposed to XO-generated oxyradicals. Note that the endothelium is recognized to be a key site of oxidant generation and attack. Our findings in vitro and in vivo support the interpretation that STS is a cardioprotective substance, and that it may exert a beneficial effect on the clinically important vascular endothelium.
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PMID:Effect of sodium tanshinone IIA sulfonate in the rabbit myocardium and on human cardiomyocytes and vascular endothelial cells. 827 65

Oxidant injury to pulmonary vascular endothelium is an important factor in the pathogenesis of acute lung injury. Oxidant injury to other cell types has been reported to alter the function of Na-K-adenosinetriphophatase (ATPase) an enzyme important in maintenance of cellular ionic homeostasis and in transport of ions across biological membranes. We investigated the effect of H2O2 (0.001-10 mM) or xanthine (X) (15.2 micrograms/ml) plus xanthine oxidase (XO) (0.0153 U/ml) on the Na-K pump activity of cultured bovine pulmonary arterial endothelial cells (PAECs). We used a functional assay, using 86RbCl as a tracer for K+ and expressing Na-K pump activity as ouabain-inhibitable K+ uptake. Our results demonstrate that H2O2 and X/XO stimulate Na-K pump activity of bovine PAECs, an effect prevented by catalase. In addition, we assessed the affinity, number, and turnover of [3H]ouabain binding sites on intact endothelial monolayers and found that H2O2 increased affinity to [3H]ouabain, decreased the number of binding sites, and increased the rate of pump turnover. Influx of 22Na increased in response to a nonlytic concentration of H2O2. Cell injury, as assessed by 51Cr release, adherent cell number, and phase-microscopic morphology, was not observed after 30-min incubations with the lowest dose (1 mM) of H2O2 effective in stimulating Na-K pump activity, or after incubation with X/XO. Na-K pump inhibition by ouabain significantly increased the 51Cr release caused by H2O2 or by X/XO, suggesting that the increase in Na-K pump activity may be a compensatory response to the cellular alterations produced by H2O2. Incubation with H2O2 decreased cell ATP content, an effect which was not prevented by coincubation with ouabain. In summary, these results show that H2O2 increases Na-K pump activity of PAECs, an effect mediated, at least in part, by increased intracellular [Na] and by an increased rate of pump turnover. It is possible that the increased pump activity may be an early marker of endothelial cell perturbation.
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PMID:Hydrogen peroxide stimulates sodium-potassium pump activity in cultured pulmonary arterial endothelial cells. 827 77

Hyperpermeability is the crux of pathogenesis of sudden lung edema in many pulmonary disorders, especially in acute lung injury and acute respiratory distress syndrome (ARDS). Using our modified method for assessment of pulmonary vascular permeability, we observed the effects of xanthine with xanthine oxidase (X-XO) perfused in rat pulmonary artery and the protection of vasoactive intestinal polypeptide (VIP) against the injury of pulmonary vascular permeability. After addition of xanthine oxidase in the perfusate reservoir containing xanthine, 125I-albumin leak index (125I-ALI) was remarkably increased while peak airway pressure (Paw) showed no significant increase, and perfusion pressure of pulmonary artery (Ppa) and lung wet/dry weight ratio (W/D) were only slightly increased. Xanthine plus xanthine oxidase also increased thromboxane B2 (TX B2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in the perfusate. Treatment with VIP obviously reduced or totally prevented all signs of injury. Simultaneously, VIP also diminished or abolished the associated generation of arachidonate products. The results indicated that VIP has potent protective activity against injury of pulmonary vascular permeability and may be a physiological modulator of inflammatory damage to vascular endothelium associated with toxic oxygen metabolites.
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PMID:[Vasoactive intestinal polypeptide prevents injury of pulmonary vascular permeability due to xanthine with xanthine oxidase]. 857 46

Hyperpermeability is a crux of pathogenesis of sudden lung edema in many pulmonary disorders, especially in acute lung injury and adult respiratory distress syndrome (ARDS). Using our modified method for assessment of pulmonary vascular permeability, we observed the effects of xanthine with xanthine oxidase (X-XO) perfused in rat pulmonary artery and the protection of vasoactive intestinal polypeptide (VIP) against the injury of pulmonary vascular permeability. After addition of xanthine oxidase in the perfusate reservoir containing xanthine, 125I-albumin leak index (125IALI) was remarkably increased while peak airway pressure (Paw) was not significantly increased, and perfusion pressure of pulmonary artery (Ppa) and lung wet/dry weight ratio (W/D) were only slightly increased. Xanthine plus xanthine oxidase also increased thromboxane B2 (TX B2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in the perfusate. Treatment with VIP obviously reduced or totally prevented all signs of injury. Simultaneously, VIP also diminished or abolished the associated generation of arachidonate products. The results indicated that VIP has potent protective activity against injury of pulmonary vascular permeability and may be a physiological modulator of inflammatory damage to vascular endothelium associated with toxic oxygen metabolites.
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PMID:Vasoactive intestinal polypeptide prevents injury of pulmonary vascular permeability due to xanthine with xanthine oxidase. 858 Apr 82

Nitric oxide release is induced in many cells, including vascular endothelium, as part of the host response to inflammation. Nitric oxide synthase activity is increased in patients with sepsis, associated with increased oxidant demands and decreased antioxidant protection. We used a human vascular endothelial cell line to investigate the influence of antioxidants on nitric oxide synthase activity. Cells were cultured to confluence and incubated with interferon gamma, tumor necrosis factor, and lipopolysaccharide in the combined presence of the antioxidants ascorbic acid, Trolox, catalase, or superoxide dismutase, singly and in combination, for 48 h. Additionally, some cells were incubated with hypoxanthine-xanthine oxidase or a nitric oxide donor. Nitric oxide synthase activity was upregulated by cytokine exposure (p < .0005). Ascorbic acid and superoxide dismutase/ catalase resulted in decreased enzyme activity (p < .05). Superoxide anion release from xanthine oxidase caused increased activity (p < .05) and exogenous nitric oxide tended to suppress synthase activity. We suggest that antioxidants scavenge superoxide anion, enabling feedback inhibition of nitric oxide synthase activity by nitric oxide, and thus reducing enzyme activity. Exogenous nitric oxide also has a similar effect. Superoxide generation suppresses this feedback inhibition. This study has important implications in patients with sepsis in whom nitric oxide synthase inhibitor therapy is currently under investigation.
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PMID:Regulation of nitric oxide synthase activity in cultured human endothelial cells: effect of antioxidants. 879 Oct 97

Xanthine oxidoreductase (XDH + XO, EC 1.2.3.2) is released into the circulation from organs rich in XO activity. Herein we report the specific high affinity binding of XO to glycosaminoglycans (GAGs) and the preferential association of XO with heparin, compared with heparan sulfate, chondroitin sulfate, and dematan sulfate. The binding of XO to Sepharose 6B-conjugated heparin (HS6B) occurs at physiological ionic strength and increased with pH, with Scatchard analysis revealing a nonlinear binding pattern at pH 7.4. The dissociation constant (Kd) for XO binding was 0.4 to 1.8 x 10(-7) M, similar to the heparin-reversible binding of lipoprotein lipase to vascular endothelium. The binding energy of 9-13 kcal/mol was concordant with noncovalent electrostatic interactions. Xanthine oxidase immobilization to HS6B rendered a catalytically active enzyme from that had kinetic characteristics distinct from XO in free solution. While the Km and Ki for xanthine in phosphate buffer at pH 7.4 were 3 microM and 1.6 mM, respectively, for free XO, they were 15 microM and 2.8 mM for immobilized XO. Inhibition constants for guanine and uric acid were also increased upon XO binding to HS6B. Changes in kinetic parameters were related to a real and not apparent decrease in binding affinity for substrate and inhibitors and were not due to diffusion-controlled processes within the gel matrix. Changes in Km and Ki for xanthine also had a significant influence on the relative quantities of O2.- and H2O2 generated by a given substrate concentration. Superoxide formed by HS6B-bound XO was partially consumed within the gel microenvironment which electrostatically excluded CuZn SOD. Immobilization of XO increased the half-life of enzyme activity in buffer and in the absence of substrate from 67 to 120 h at 4 degrees C. These data indicate that binding to cell surfaces will strongly influence the catalytic properties, oxidant producing capacity, and stability of XO.
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PMID:Xanthine oxidase binding to glycosaminoglycans: kinetics and superoxide dismutase interactions of immobilized xanthine oxidase-heparin complexes. 905 42


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