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)

In this study bovine pulmonary artery endothelial cells (BPAEC) were used as a model system to investigate the effects of the hypoxanthine-xanthine oxidase (HXXO) oxygen radical donor system on ET-1 secretion into pulmonary vasculature. Incubation of BPAEC with HXXO for 4 h caused a significant reduction in ET-1 secretion, which was significantly offset by allopurinol or catalase, but not by Cu/Zn superoxide dismutase (SOD). ET-1 secretion was also reduced by H2O2, and this effect was again significantly offset by catalase. XO alone also reduced ET-1 secretion, but to a significantly lesser degree than did HXXO, and this effect was not offset by allopurinol, catalase, or SOD. None of the oxidant treatments were associated with a loss of immunoreactive ET-1 from endothelial cell medium containing synthetic peptide. The HXXO- and H2O2-mediated reductions in ET-1 secretion were accompanied by evidence of reduced cell viability. This loss of viability was absent when cells were treated with HXXO + catalase, allopurinol, or mercaptopropionyl glycine, but not when SOD was present. We conclude that under conditions of oxidative stress, the pulmonary vascular endothelium responds by secreting less ET-1. This may be relevant to its vasodilator functions in the pulmonary vasculature, which would therefore be compromised when the endothelium is exposed to oxidant stress.
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PMID:Cytotoxicity-associated effects of reactive oxygen species on endothelin-1 secretion by pulmonary endothelial cells. 964 Dec 61

Both reactive oxygen species (ROS) and endothelin-1 (ET- 1) have been implicated in the pathophysiology of diabetic nephropathy. The interrelationship between them, however, has not been documented in this disease. To determine whether ROS regulates ET-1 production in diabetic kidneys, we examined the in vitro and in vivo effects of ROS donors and scavengers on ET-1 production of diabetic rat glomeruli. For in vitro study, the glomeruli were isolated with a sieving method from streptozotocin-induced diabetic rats and killed at 1 week, 1 month, and 3 months, respectively. Superoxide was measured by a spectrophotometer, and ET-1 was measured by radioimmunoassay. The results demonstrated that the basal production levels of superoxide and ET-1 were higher in diabetic glomeruli than in normal glomeruli in vitro. There was a positive correlation between the production of superoxide and ET-1 in diabetic glomeruli. The basal ET-1 production was markedly attenuated by ROS scavengers including superoxide dismutase, catalase, dimethyl sulfoxide, and deferoxamine in diabetic glomeruli. Exogenous ROS generated by xanthine/xanthine oxidase significantly enhanced ET-1 generation by both diabetic and normal glomeruli. A high glucose concentration (500 mg/dL) in vitro increased ET-1 production by normal glomeruli but not diabetic glomeruli, and insulin partly suppressed ET- 1 production by diabetic glomeruli. The in vivo study demonstrated that when diabetic rats were injected daily with superoxide dismutase or catalase after diabetes was induced, the basal production of ET-1 was markedly attenuated after 1 week and 1 month, respectively. These results indicate that exogenously or endogenously derived ROS can enhance ET-1 production by diabetic rat glomeruli and that ROS scavengers suppress ET- 1 production both in vitro and in vivo. The effects of ROS on ET-1 production of diabetic glomeruli may be partly caused by the effect of hyperglycemia or insulin deficiency.
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PMID:Reactive oxygen species enhances endothelin-1 production of diabetic rat glomeruli in vitro and in vivo. 1077 44

Endothelins, nitric oxide, and oxygen-derived free radicals decisively regulate vascular tone. An imbalance in the biosynthesis of these substances in pathophysiologic conditions may trigger vasospasm and promote the development of atherosclerosis. Previous studies have shown that oxygen-derived free radicals can increase the synthesis of endothelin-1 in cultured endothelial cells. Interestingly, conditions of increased oxidative stress within smooth muscle cells as induced by angiotensin II infusion or hypercholesterolemia have been shown to be associated with increased autocrine synthesis of endothelin-1. Because endothelin-1 formed in smooth muscle cells can trigger hypersensitivity to vasoconstrictors, we tested whether oxidative stress per se may affect endothelin expression in vascular smooth muscle cells. Cultured human coronary artery smooth muscle cells were exposed to oxidative stress generated by the xanthine/xanthine oxidase reaction or by hydrogen peroxide. Preproendothelin-1 mRNA content was quantitated by means of quantitative polymerase chain reaction and endothelin-1 protein was measured by radioimmunoassay. Incubation with xanthine/xanthine oxidase significantly increased preproendothelin-1 mRNA synthesis, whereas GAPDH remained unchanged. Likewise, xanthine/xanthine oxidase also led to a dose-dependent increase of intracellular endothelin-1. The increase in ET-1 expression induced by xanthine/xanthine oxidase was significantly inhibited by superoxide dismutase but not by catalase. We conclude that oxygen-derived free radicals can stimulate the synthesis of endothelin-1 in endothelial and vascular smooth muscle cells by increasing preproendothelin-1 mRNA content and that this effect is mediated predominantly by superoxide anions. We therefore have identified a new mechanism in the interaction of oxidative stress and endothelin-1 expression in smooth muscle cells that may have important implications in diseases such as atherosclerosis and hypertension.
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PMID:Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells. 1144 2

A dysregulated metabolism of oxygen-derived free radicals, nitric oxide and endothelin-1(ET-1) in conditions such as hypercholesterolaemia or hypertension may promote the development of atherosclerosis. We therefore subjected cultured human umbilical vein endothelial cells and coronary artery smooth muscle cells to oxidative stress induced by xanthine oxidase or hydrogen peroxide and observed alterations in ET-1 metabolism. Incubation with oxygen-derived free radicals increased preproET-1 promoter activity, ET-1 mRNA synthesis and big ET-1 concentrations in both cell types. This interaction of oxidative stress and ET-1 expression may be relevant in atherogenic conditions such as hypercholesterolaemia and hypertension since our data indicate that oxidative stress further aggravates the injurious effects attributed to ET-1.
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PMID:Endothelin-1 mRNA and protein in vascular wall cells is increased by reactive oxygen species. 1219 80

We previously found that human chymase cleaves big endothelins (ETs) at the Tyr(31)-Gly(32) bond and produces 31-amino acid ETs (1-31), without any further degradation products. In the present study, we investigated the effects of various antioxidants on the ET-1 (1-31)-induced change in intracellular signaling and proliferation of cultured rat aortic smooth muscle cells (RASMC). ET-1 (1-31) stimulated rapid and significant activation of the mitogen-activated protein (MAP) kinase family, i.e. extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK, in RASMC to an extent similar to that of ET-1. All of the antioxidants examined, i.e. N-acetyl-L-cysteine (NAC), diphenyleneiodonium chloride (DPI), and L-(+)-ascorbic acid (ascorbic acid), inhibited both ET-1 (1-31)- and ET-1-induced JNK and p38 MAPK activation but not ERK1/2 activation. Electron paramagnetic resonance (EPR) spectroscopy measurements revealed that NAC, DPI, and ascorbic acid inhibited xanthine oxidase-induced superoxide (O(2)(.-)) generation in a cell-free system. ET-1 (1-31) in addition to ET-1 increased the generation of cellular reactive oxygen species (ROS) in RASMC. ET-1 (1-31)- and ET-1-induced cellular ROS generation was inhibited similarly by NAC, DPI, and ascorbic acid in RASMC. Gel-mobility shift analysis showed that ET-1 (1-31) and ET-1 caused an increase in activator protein-1 (AP-1)-DNA binding activity in RASMC that was inhibited by the above three antioxidants. ET-1 (1-31) increased [3H]thymidine incorporation into cells to an extent similar to that of ET-1. This ET-1 (1-31)-induced increase in [3H]thymidine incorporation was also inhibited by NAC and DPI, but not by ascorbic acid. These results suggest that antioxidants inhibit ET-1 (1-31)-induced RASMC proliferation by inhibiting ROS generation within the cells. The underlying mechanisms of the inhibition of cellular proliferation by antioxidants may be explained, in part, by the inhibition of JNK activation and the resultant inhibition of AP-1-DNA binding.
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PMID:Antioxidants inhibit endothelin-1 (1-31)-induced proliferation of vascular smooth muscle cells via the inhibition of mitogen-activated protein (MAP) kinase and activator protein-1 (AP-1). 1241 65

We have demonstrated recently [Callera, Touyz, Teixeira, Muscara, Carvalho, Fortes, Schiffrin and Tostes (2003) Hypertension 42, 811-817] that increased vascular oxidative stress in DOCA (deoxycorticosterone acetate)-salt rats is associated with activation of the ET (endothelin) system via ETA receptors. The exact source of ET-1-mediated oxidative stress remains unclear. The aim of the present study was to investigate whether ET-1 increases generation of ROS (reactive oxygen species) in DOCA-salt hypertension through NADPH-oxidase-dependent mechanisms. Xanthine oxidase, eNOS (endothelial nitric oxide synthase) and COX-2 (cyclo-oxygenase-2) were also examined as potential ET-1 sources of ROS as well as mitochondrial respiration. DOCA-salt and control UniNX (uninephrectomized) rats were treated with the ETA antagonist BMS182874 (40 mg.day(-1).kg(-1) of body weight) or vehicle. Plasma TBARS (thiobarbituric acid-reacting substances) were increased in DOCA-salt compared with UniNX rats. Activity of NADPH and xanthine oxidases in aorta, mesenteric arteries and heart was increased in DOCA-salt rats. BMS182874 decreased plasma TBARS levels without influencing NADPH and xanthine oxidase activities in DOCA-salt rats. Increased p22(phox) protein expression and increased p47(phox) membrane translocation in arteries from DOCA-salt by rats were not affected by BMS182874 treatment. Increased eNOS and COX-2 expression, also observed in aortas from DOCA-salt rats, was unaltered by BMS182874. Increased mitochondrial generation of ROS in DOCA-salt rats was normalized by BMS182874. ETA antagonism also increased the expression of mitochondrial MnSOD (manganese superoxide dismutase) in DOCA-salt rats. In conclusion, activation of NADPH oxidase does not seem to be the major source of oxidative stress induced by ET-1/ETA in DOCA-salt hypertension, which also appears to be independent of increased activation of xanthine oxidase or eNOS/COX-2 overexpression. Mitochondria may play a role in ET-1-driven oxidative stress, as evidenced by increased mitochondrial-derived ROS in this model of hypertension.
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PMID:Endothelin-1-induced oxidative stress in DOCA-salt hypertension involves NADPH-oxidase-independent mechanisms. 1632 76

Reactive oxygen species (ROS) are important mediators in vascular biology. Venous function, although relevant to cardiovascular disease, is still understudied. We compared aspects of ROS metabolism between a major artery (the aorta) and a major vein (the vena cava, VC) of the rat, with the hypothesis that venous ROS metabolism would be overall increased compared with its arterial counterpart. Superoxide and hydrogen peroxide (H2O2) release in basal conditions was higher in VC compared with aorta. The antioxidant capacity for H2O2 was also higher in VC than in aorta. Exogenous superoxide induced a higher contraction in VC compared with aorta. Protein expression of three major ROS metabolizing enzymes, xanthine oxidase (XO), CuZn-SOD, and catalase, was higher in VC compared with aorta. Because XO seemed a likely source of the higher VC ROS levels, we examined it further and found higher mRNA expression and activity of XO in VC compared with aorta. We also investigated the impact of XO inhibition by allopurinol on aorta and VC functional responses to norepinephrine, ANG II, ET-1, and ACh. Maximal ET-1-mediated contraction was decreased by allopurinol in VC but not in the aorta. Our results suggest that there are overall differences in ROS metabolism between aorta and VC, with the latter operating normally at a higher set point, releasing but also being able to handle, higher ROS levels. We propose XO to be an important source for these differences. The result of this particular comparison may be reflective of a general arteriovenous contrast.
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PMID:A comparison of reactive oxygen species metabolism in the rat aorta and vena cava: focus on xanthine oxidase. 1866 Apr 42

Recent data implicate oxidative stress as a mediator of pulmonary hypertension (PH) and of the associated pathological changes to the pulmonary vasculature and right ventricle (RV). Increases in reactive oxygen species (ROS), altered redox state, and elevated oxidant stress have been demonstrated in the lungs and RV of several animal models of PH, including chronic hypoxia, monocrotaline toxicity, caveolin-1 knock-out mouse, and the transgenic Ren2 rat which overexpresses the mouse renin gene. Generation of ROS in these models is derived mostly from the activities of the nicotinamide adenine dinucleotide phosphate oxidases, xanthine oxidase, and uncoupled endothelial nitric oxide synthase. As disease progresses circulating monocytes and bone marrow-derived monocytic progenitor cells are attracted to and accumulate in the pulmonary vasculature. Once established, these inflammatory cells generate ROS and secrete mitogenic and fibrogenic cytokines that induce cell proliferation and fibrosis in the vascular wall resulting in progressive vascular remodeling. Deficiencies in antioxidant enzymes also contribute to pulmonary hypertensive states. Current therapies were developed to improve endothelial function, reduce pulmonary artery pressure, and slow the progression of vascular remodeling in the pulmonary vasculature by targeting deficiencies in either NO (PDE-type 5 inhibition) or PGI(2) (prostacyclin analogs), or excessive synthesis of ET-1 (ET receptor blockers) with the intent to improve patient clinical status and survival. New therapies may slow disease progression to some extent, but long term management has not been achieved and mortality is still high. Although little is known concerning the effects of current pulmonary arterial hypertension treatments on RV structure and function, interest in this area is increasing. Development of therapeutic strategies that simultaneously target pathology in the pulmonary vasculature and RV may be beneficial in reducing mortality associated with RV failure.
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PMID:Contribution of oxidative stress to pulmonary arterial hypertension. 2116 Jun 9