Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that calcium-antagonists may reduce the development of experimental atherosclerosis, and that nifedipine may slow progression of coronary atherosclerosis in man. The mechanisms responsible for this effect are still unclear. It has been recently proposed that oxygen-free radicals can induce peroxidation of human low-density lipoproteins (LDL), and that peroxidized LDL may be an atherogenic stimulus. Chemical modified LDL are internalized by macrophages via specific cell surface receptor that was termed the scavenger receptor, and could induce foam cells transformation in vivo. Previous studies on other systems have shown that calcium-antagonists may effectively inhibit oxygen radical-induced lipid peroxidation. These drugs, though differing widely in their chemical structure, are lipophilic to various degrees and presumably would concentrate in the lipid domain of the phospholipid-rich membranes. Therefore, the aim of the present study was to investigate whether calcium-channel blockers may reduce human LDL peroxidation. Purified human LDL were exposed to oxygen radicals generated by xanthine-xanthine oxidase (18 hours) after a pre-incubation (30 min) in presence of different concentrations of nifedipine, diltiazem and verapamil. Peroxidation was measured from malonyldialdehyde production. The results show that calcium-antagonists prevent LDL peroxidation. Thus, calcium-antagonists may reduce peroxidation of human LDL in vitro, at clinically relevant concentrations. These data suggest that reduced formation of atherogenic peroxidized LDL may be an additional mechanism for the anti-atherosclerotic effects of calcium-antagonists in vivo.
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PMID:[Calcium channel blockers inhibit human low-density lipoprotein peroxidation induced by oxygen free radicals in vitro]. 129 53

1. Nilvadipine (FK 235, FR 34235) suppressed ischemia (20 min)-reflow (20 min)-induced paw edema of mice (ED30:0.4 mg/kg i.v. and 2 mg/kg p.o.). Other calcium entry blockers of dihydropyridine-type also suppressed the edema, but 30-fold higher doses were required. 2. Oral dosing of nilvadipine suppressed carrageenan-induced paw edema (ED30:15 mg/kg in rats and 20 mg/kg in mice) at a potency corresponding to that of an anti-inflammatory drug, ibuprofen. Nifedipine, nicardipine and nimodipine resulted in a suppression of 30% only with 100 mg/kg oral dosing in rats. Nitrendipine, diltiazem and verapamil were without effect. 3. Nilvadipine inhibited superoxide radical (O-2production from xanthine oxidase (XOD) both with lactate dehydrogenase + NADH method and cytochrome c method (IC50:90 and 100 micrograms/ml, respectively). Nifedipine and nicardipine showed some inhibition, but the other calcium entry blockers failed to inhibit significantly even at 320 micrograms/ml. As uric acid formation was not reduced by the tested drugs, the inhibitory action might be due to their O-2scavenging effects. 4. Superoxide production of neutrophils from casein-induced peritoneal fluid in rats was most strongly inhibited by nilvadipine when the cells were stimulated by a calcium ionophore, A23187 (IC50:4 micrograms/ml). Inhibition by this drug when stimulated by f-methonyl-leucyl-phenylalanine and phorbol myristate acetate was less effective (IC50:20 and 30 micrograms/ml, respectively). Nifedipine and nicardipine inhibited neutrophil O-2production at higher concentrations (30-200 micrograms/ml) with all stimulants. Inhibitory actions by other drugs were weak. 5. Triggering of atherosclerosis depends largely on the oxidative stress on blood vessels after recently established concept.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition by nilvadipine of ischemic and carrageenan paw edema as well as of superoxide radical production from neutrophils and xanthine oxidase. 165 7

Oxygen free radicals (OFR) are thought to mediate ischemia-reperfusion injury to endothelium of heart, lung, brain, liver, and kidney and contribute to development of atherosclerosis, pulmonary O2 toxicity, and adult respiratory distress syndrome. Increased cytosolic free Ca2+ (Cai2+) has been proposed as a mechanism of injury from oxidative stress, yet the pathways by which an increase in Cai2+ may cause OFR-mediated endothelial cell injury remain unknown. Using multiparameter digitized video microscopy and the fluorescent probes, fura-2 acetoxymethyl ester and propidium iodide, we measured Cai2+ and cell viability in human umbilical endothelial cells during oxidative stress with xanthine (50 microM) plus xanthine oxidase (40 mU/ml). Oxidative stress caused a sustained increase in Cai2+ from a resting level of 90-100 nM to near 500 nM, which was preceded by formation of plasma membrane blebs. The increase in Cai2+ was prevented by removal of extracellular Ca2+ (Cao2+). Prevention of the increase in Cai2+ was associated with prolonged cell viability. Readdition of Cao2+ resulted in an immediate large increase in Cai2+ and rapid onset of cell death. The protease inhibitors, leupeptin and pepstatin, delayed the increase in Cai2+ and prolonged cell viability. The results are consistent with the hypothesis that endothelial cell injury due to oxidative stress may be the result of Cai2+ influx and resultant activation of Ca(2+)-dependent proteases.
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PMID:Cytosolic free Ca2+ and proteolysis in lethal oxidative injury in endothelial cells. 195 73

A segment of fresh rabbit thoracic aorta (RbA) was turned inside out and superfused (1.5 ml/min) with citrated (3.8%) or heparinized (10 U/ml) blood of rabbit and the superfusate was discarded. RbA gained in weight due to deposition of thrombi on its endothelial surface. These thrombi were mainly composed of platelets. The interaction between platelets and endothelium was augmented in RbAs from animals with atherosclerosis and in RbAs pretreated with aspirin (110 microM) or 15-HPETE (150 microM) or by the enzymatic system generating oxygen free radicals (xanthine:xanthine oxidase - 100 microM: 0.1 U/ml). On the other hand, this interaction was impaired by superoxide dismutase (20 U/ml) or catalase (0.2 U/ml). Finally, the dissipation of thrombi by thromboxane A2-synthetase inhibitor--dazoxiben was found to be related to an increase in endothelial generation of prostacyclin.
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PMID:A biological method for studying the interaction between platelets and vascular endothelium. 210 94

Transitional metals, particularly iron, markedly potentiate oxidant damage to isolated cell organelles. However, determining the probable importance of iron in damage to intact cells is difficult because of our inability experimentally to increase the cell content of this transition metal. We now report that heme is a uniquely effective iron delivery vehicle, capable of loading large amounts of potentially reactive iron into intact cells. We find that endothelial cells in vitro rapidly incorporate free heme and this heme-loading sensitizes endothelium to oxidant-mediated cytotoxicity caused by hydrogen peroxide, the hypoxanthine/xanthine oxidase system, or phorbol-stimulated PMN. Although the precise mechanism of the heme-aggravated cytotoxicity is not yet known, it closely parallels amplified lipid peroxidation in endothelial cell membranes suggesting the importance of lipid injury. Hemopexin, by complexing heme, protects endothelial cells from activated PMN, but only if added simultaneously. The hydrophobic iron chelator and antioxidant, U74500A, abrogates heme-augmented hydrogen peroxide and PMN-mediated endothelial damage. Such compounds, therefore, may have therapeutic potential in one or more of the listed clinical syndromes. We speculate that exposure of endothelium to free heme may potentiate vascular damage in various clinical syndromes, including acute renal failure after massive intravascular hemolysis, crush injuries, reperfusion after myocardial infarction (perhaps secondary to cardiac myoglobin release), retrolental fibroplasia associated with neonatal hemopexin deficiency, and, perhaps, atherosclerosis involving sites of turbulence that may trigger minor red blood cell lysis.
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PMID:Heme uptake by endothelium synergizes polymorphonuclear granulocyte-mediated damage. 213 29

Toxic oxygen metabolites can damage endothelial cells and may play an important role in the initiation and progression of atherosclerotic lesions. Since the antithrombotic drug heparin, interacts with endothelium, we wished to determine if heparin would protect endothelial cells from free radical injury. Endothelial cell injury was produced by the addition of xanthine and xanthine oxidase to cultured cells and assessed by changes in cell viability and release of lactate dehydrogenase (LDH) to the media. Pretreatment with heparin 24 h prior to addition of xanthine and xanthine oxidase significantly decreased cell damage. We suggest that heparin (and related compounds) can protect endothelium from free radical damage, and is therefore prophylactic for ischemic and inflammatory injury, and the development and progression of atheroma.
Atherosclerosis 1990 Jul
PMID:Heparin protects cultured arterial endothelial cells from damage by toxic oxygen metabolites. 239 Jan 35

The presence of antibodies of the IgA class against dietary antigens (bovine IgG (BGG), beta-lactoglobulin, casein, alpha-lactalbumin and xanthine oxidase, chicken ovalbumin and crude gliadin) was checked in the sera of 23 severely atherosclerotic subjects (ATS) and 20 highly selected controls (C). In these subjects an association between serum IgA levels and atherosclerosis had previously been shown. Determinations were performed by a micro-ELISA method and results were expressed as absorbances at 405 nm x 1000. Higher levels of IgA antibodies were found in ATS with respect to C against beta-lactoglobulin (respectively, 113.4 +/- 152.4 (1 SD) vs. 40.0 +/- 34.2; P less than 0.005) and casein (69.8 +/- 35.5 vs. 52.4 +/- 27.5; P less than 0.05). There was no difference in IgG and IgM against these 2 proteins between the 2 groups. Significant differences of prevalence of IgA antibodies were found for the following antigens: beta-lactoglobulin (4 C and 16 ATS over the limit value of 51; P less than 0.002), xanthine oxidase (1 C and 9 ATS over 289; P less than 0.01), BGG (7 C and 17 ATS over 87; P less than 0.02) and casein (5 C and 14 ATS over 60; P less than 0.02). These data suggest an association between anti-milk IgA antibodies and atherosclerosis. Its relevance and significance deserves further investigation.
Atherosclerosis 1989 Jun
PMID:Association of serum IgA antibodies to milk antigens with severe atherosclerosis. 275 57

Oxidative damage to the vascular endothelium may play an important role in the pathogenesis of atherosclerosis and aging, and may account in part for reduced vascular prostacyclin (PGI2) synthesis associated with both conditions. Using H2O2 to induce injury, we investigated the effects of oxidative damage on PGI2 synthesis in cultured endothelial cells (EC). Preincubation of EC with H2O2 produced a dose-dependent inhibition (inhibitory concentration [IC50] = 35 microM) of PGI2 formation from arachidonate. The maximum dose-related effect occurred within 1 min after exposure although appreciable H2O2 remained after 30 min (30% of original). In addition, H2O2 produced both a time- and dose-dependent injury leading to cell disruption, lactate dehydrogenase release, and 51Cr release from prelabeled cells. However, in dramatic contrast to H2O2 effects on PGI2 synthesis, loss of cellular integrity required doses in excess of 0.5 mM and incubation times in excess of 1 h. The superoxide-generating system, xanthine plus xanthine oxidase, produced a similar inhibition of PGI2 formation. Such inhibition was dependent on the generation of H2O2 but not superoxide in that catalase was completely protective whereas superoxide dismutase was not. H2O2 (50 microM) also effectively inhibited basal and ionophore A23187 (0.5 microM)-stimulated PGI2 formation. However, H2O2 had no effect on phospholipase A2 activity, because ionophore A23187-induced arachidonate release was unimpaired. To determine the effects on cyclooxygenase and PGI2 synthase, prostaglandin products from cells prelabeled with [3H]arachidonate and stimulated with ionophore A23187, or products formed from exogenous arachidonate were examined. Inhibition of cyclooxygenase but not PGI2 synthase was observed. Incubation of H2O2-treated cells with prostaglandin cyclic endoperoxide indicated no inhibition of PGI2 synthase. Thus, in EC low doses of H2O2 potently inhibit cyclooxygenase after brief exposure whereas larger doses and prolonged exposure are required for classical cytolytic effects. Surprisingly, PGI2 synthase, which is known to be extremely sensitive to a variety of lipid peroxides, is not inhibited by H2O2. Lipid solubility, enzyme location within the EC membrane, or the local availability of reducing factors may explain these results, and may be important determinants of the response of EC to oxidative stress.
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PMID:Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic endothelial cells. 299 39

The theory that consumption of homogenized milk containing active xanthine oxidase is a causative factor in development of atherosclerosis is reviewed. Biologically available xanthine oxidase in consumed milk products may be absorbed in the small intestine and enter the blood stream. However, there appears to be no unequivocal evidence that the absorbed enzyme has any pathological effects that may contribute to development of atherosclerotic heart disease.
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PMID:Homogenized milk and atherosclerotic disease: a review. 635 Mar 92

Exocytosis from Weibel-Palade bodies, the secretory granules of vascular endothelial cells, causes the rapid release of von Willebrand factor (vWF), an adhesive glycoprotein involved in primary hemostasis, and cell surface expression of P-selectin, a membrane protein involved in neutrophil binding. Thus, exocytosis may represent a link between hemostasis and inflammation. We investigated the effect of reactive oxygen intermediates (ROIs) on vWF secretion. Incubation of cultured endothelial cells with xanthine oxidase (XO), which generates superoxide anions (O2-), induces a potent, rapid secretory response. However, vWF release was not observed in response to H2O2. Extracellular, subendothelial vWF deposits typically seen after exocytosis from Weibel-Palade bodies were observed after exposure to XO. XO caused a rapid, sustained increase in intracellular free calcium concentration ([Ca2+]i). vWF secretion was markedly inhibited by BAPTA-AM, a cell-permeant calcium chelator. Removal of extracellular calcium did not inhibit vWF release, although the sustained phase of the [Ca2+]i increase was suppressed. These results suggest that XO-induced vWF release is mediated by the initial increase in [Ca2+]i which is caused by calcium mobilization from intracellular stores rather than by calcium influx. Exocytosis from Weibel-Palade bodies may contribute to the pathogenic effect of ROIs in atherosclerosis and inflammation.
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PMID:Reactive oxygen intermediates induce regulated secretion of von Willebrand factor from cultured human vascular endothelial cells. 775 49


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