Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Reactive oxygen species (ROS) released acutely in large amounts have been traditionally implicated in the cell death associated with myocardial infarction or reperfusion injury. These ROS can be released from the cardiac myocyte mitochondria, xanthine oxidase, and the phagocytic nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase. Interestingly, the chronic release of ROS has been recently linked to the development of left ventricular hypertrophy and heart failure progression. The chronic release of ROS appears to derive from the nonphagocytic NAD(P)H oxidase and mitochondria. Experimental data are accumulating suggesting that the release of ROS is required for the normal, physiologic activity of cardiac cells, but abnormal activation of the nonphagocytic NAD(P)H oxidase in response to neurohormones (angiotensin II, norepinephrine, tumor necrosis factor-a) has been shown to contribute to cardiac myocyte hypertrophy. Furthermore, the fibrosis, collagen deposition, and metalloproteinase activation involved in the remodeling of the failing myocardium are dependent on ROS released during the phenotypic transformation of fibroblasts to myofibroblasts associated with progression of end-stage heart failure. Future studies are necessary to identify the sources, mechanisms of activation of NAD(P)H oxidases, and downstream signaling targets implicated in the progression of chronic heart failure.
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PMID:Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. 1204 81

Complement (C) activation is believed to play an adverse role in several chronic degenerative disease processes, including atherosclerosis, myocardial infarction and Alzheimer's disease. We developed several in vitro quantitative assays to evaluate processes which activate C in human serum, and to assess candidates which might block that activation. Binding of C-reactive protein (CRP) to immobilized cell surfaces was used as a tissue-based method of activation, while immunoglobulin G in solution was used as a surrogate antibody method. Activation was assessed by deposition of C fragments on fixed cell surfaces, or by capture of C5b-9 from solution. We observed that several cell lines, including SH-SY5Y, U-937, THP-1 and ECV304, bound CRP and activated C following attachment of cells to a plastic surface by means of air drying. Treatment of human neuroblastoma SH-SY5Y cells with the reactive oxygen intermediates generated by xanthine (Xa) - xanthine oxidase (XaOx) prior to air drying or by hydrogen peroxide solutions after air drying, enhanced C activation, possibly through oxidation of the cell lipid membrane. Several C inhibitors were tested for their effectiveness in blocking these systems. Pentosan polysulphate (PPS), an orally active agent, blocked C activation in the same concentration range of 1-1000 microg/ml as heparin, dextran sulphate, compstatin and fucoidan. PPS may have practical application as a C inhibitor.
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PMID:Effects of C-reactive protein and pentosan polysulphate on human complement activation. 1210 Jul 26

Oxidative stress is a hallmark of systemic illnesses, including heart failure. Nevertheless, the overall importance of radical production in the heart remains conjectural; is it merely a marker of illness, or can intervention alter the progression of disease? This question was addressed by blocking xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in animal models of heart failure. In a randomized prospective trial design, we administered the XO inhibitor allopurinol orally to mice that had undergone massive myocardial infarction (MI). Cardiac XO activity was elevated in untreated mice after MI; allopurinol suppressed the XO activity to levels comparable to those in sham-operated mice. Eighty-one percent of untreated mice died of advanced heart failure over 2 to 4 weeks of follow-up. Survival doubled in the allopurinol-treated mice, whereas cardiac contractile function (both in vivo and in isolated muscle) was markedly improved. Response to isoproterenol was restored to near-normal levels in the allopurinol group but was attenuated in untreated mice. Oxidative modifications to proteins were prevented in the allopurinol-treated mice. Our findings indicate that targeted blockade of just one source of oxidants, XO, impacts dramatically on the progression of postischemic cardiomyopathy in mice and prevents oxidative protein modifications.
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PMID:Chronic treatment with allopurinol boosts survival and cardiac contractility in murine postischemic cardiomyopathy. 1549 28

Reactive oxygen species (ROS), as superoxide and its metabolites, have important roles in vascular homeostasis as they are involved in various signaling processes. In many cardiovascular disease states, however, the release of ROS is increased. Uncontrolled ROS production leads to impaired endothelial function and consequently to vascular dysfunction. This review focuses on two clinical conditions associated with elevated ROS levels: ischemia/reperfusion and nitrate tolerance. Injury caused by ischemia/reperfusion is an important limitation of transplantations, and complicates the management of stroke and myocardial infarction. Nitrates, which are used to treat transient myocardial ischemia (angina pectoris), decrease in efficacy in long-term continuous administration. There are several enzyme systems, such as xanthine oxidase, cyclooxygenase, uncoupled endothelial nitric oxide synthase, NAD(P)H oxidase, cytochrome P450 and the mitochondrial electron transport chain, which are responsible for the increased vascular production of superoxide. The contribution of particular ROS producing enzymes and the effect of antioxidant treatment are discussed in both pathological conditions.
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PMID:Endothelial dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrate tolerance. 1563 16

Nitrite represents a circulating and tissue storage form of NO whose bioactivation is mediated by the enzymatic action of xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin, myoglobin, and tissue heme proteins. Because the rate of NO generation from nitrite is linearly dependent on reductions in oxygen and pH levels, we hypothesized that nitrite would be reduced to NO in ischemic tissue and exert NO-dependent protective effects. Solutions of sodium nitrite were administered in the setting of hepatic and cardiac ischemia-reperfusion (I/R) injury in mice. In hepatic I/R, nitrite exerted profound dose-dependent protective effects on cellular necrosis and apoptosis, with highly significant protective effects observed at near-physiological nitrite concentrations. In myocardial I/R injury, nitrite reduced cardiac infarct size by 67%. Consistent with hypoxia-dependent nitrite bioactivation, nitrite was reduced to NO, S-nitrosothiols, N-nitros-amines, and iron-nitrosylated heme proteins within 1-30 minutes of reperfusion. Nitrite-mediated protection of both the liver and the heart was dependent on NO generation and independent of eNOS and heme oxygenase-1 enzyme activities. These results suggest that nitrite is a biological storage reserve of NO subserving a critical function in tissue protection from ischemic injury. These studies reveal an unexpected and novel therapy for diseases such as myocardial infarction, organ preservation and transplantation, and shock states.
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PMID:Cytoprotective effects of nitrite during in vivo ischemia-reperfusion of the heart and liver. 1584 Dec 16

Heart failure is the major cause of hospitalization, morbidity and mortality worldwide. Previous experimental and clinical studies have suggested that there is an increased production of reactive oxygen species (ROS: superoxide, hydrogen peroxide, hydroxyl radical) both in animals and in patients with acute and chronic heart failure. The possible source of increased ROS in the failing myocardium include xanthine and NAD(P)H oxidoreductases, cyclooxygenase, the mitochondrial electron transport chain and activated neutrophils among many others. The excessively produced nitric oxide (NO) derived from NO synthases (NOS) has also been implicated in the pathogenesis of chronic heart failure (CHF). The combination of NO and superoxide yields peroxynitrite, a reactive oxidant, which has been shown to impair cardiac function via multiple mechanisms. Increased oxidative and nitrosative stress also activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP), which importantly contributes to the pathogenesis of cardiac and endothelial dysfunction associated with myocardial infarction, chronic heart failure, diabetes, atherosclerosis, hypertension, aging and various forms of shock. Recent studies have demonstrated that pharmacological inhibition of xanthine oxidase derived superoxide formation, neutralization of peroxynitrite or inhibition of PARP provide significant benefit in various forms of cardiovascular injury. This review discusses the role of oxidative/nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure.
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PMID:Role of oxidative-nitrosative stress and downstream pathways in various forms of cardiomyopathy and heart failure. 1602 19

After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, 1H MRI and 31P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P < 0.005), and the LV ejection fraction (EF) decreased (14 +/- 9%) compared with control hearts (59 +/- 8%, P < 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 +/- 0.6) compared with control animals (2.1 +/- 0.5, P < 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 +/- 9%, P = 0.01), and normalized cardiac PCr/ATP (2.0 +/- 0.5, P < 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction.
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PMID:Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts. 1618 26

Recovery from myocardial infarction is associated with a series of alterations in heart structure and function, collectively known as cardiac remodelling, which play a major role in the subsequent development of heart failure. Early remodelling involves infarct scar formation in the ischaemic zone whereas subsequent ventricular remodelling affects mainly the viable non-infarcted myocardium with especially profound alterations in the extracellular matrix. There is growing evidence for a role of oxidative stress and redox signalling in the processes underlying cardiac remodelling. Reactive oxygen species are a group of highly reactive molecules which have the potential to modulate several biological processes as well as cause tissue damage and dysfunction. Their effects can be beneficial or deleterious, depending on the concentrations produced, the site of production, and the overall redox status of the cell. Reactive oxygen species can be generated by all cardiovascular cell types. Under pathophysiological conditions, major enzymatic sources appear to be mitochondria, xanthine oxidase and the non-phagocytic NADPH oxidases. In this review, we outline the mechanisms underlying the progression of early and late cardiac remodelling with particular focus on the role of oxidative stress and the potential sources of reactive oxygen species which may be involved.
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PMID:Role of oxidative stress in cardiac remodelling after myocardial infarction. 1635 83

Reperfusion injury causes oxidative stress thereby resulting in an imbalance between oxidant-antioxidant systems. In the present communication, the effect of ascorbic acid supplementation has been studied on certain oxidant and antioxidant parameters in the blood of the patients with myocardial infarction before and after thrombolysis. In patients after thrombolysis, the activity of antioxidant enzyme, superoxide dismutase, in the blood was found to be significantly reduced where as the activity of the oxidant enzyme, xanthine oxidase, was found to be significantly increased. Malondialdehyde levels, the index of free radical mediated damage, was also found to be significantly elevated in thrombolysed patients compared to the patients before thrombolysis. Supplementation of vitamin C to the post reperfusion patients restored these parameters back to normal or near normal levels.
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PMID:Effect of ascorbic acid supplementation on certain oxidative stress parameters in the post reperfusion patients of myocardial infarction. 1671 65

Zofenopril ameliorates experimental cardiac ischemia/reperfusion (IR) injury in animal models and exhibits beneficial cardiovascular effects in patients with myocardial infarction. The objective of the present research was to investigate whether zofenopril can protect against renal IR injury. Rats were divided into 4 experimental groups: (a) control, (b) IR (60 min of ischemia followed by 24 hr of reperfusion), (c) zofenopril (15 mg/kg/day for 2 days), and (d) zofenopril+IR. All of the rats underwent right nephrectomy, and the rats in the IR and zofenopril+IR groups also underwent IR.then the left kidneys were removed for biochemical analyses and microscopic examination. There were no abnormalities in the biochemical and microscopic findings in the preoperative right kidneys. The lipid peroxidation, protein oxidation, and nitric oxide levels as well as xanthine oxidase and myeloperoxidase activities were increased and the catalase and superoxide dismutase activities were decreased in the IR group; zofenopril treatment prevented these changes (p <0.05). In the IR group, the kidney sections showed severe acute tubular damage including brush border loss, nuclear condensation, cytoplasmic swelling, and loss of nuclei; in the zofenopril+IR group, the normal glomerular morphology was preserved and there was slight edema of the tubular cells. The renal damage score was significantly reduced in the zofenopril+IR group vs the IR group (p <0.05). In conclusion, IR injury caused oxidative damage in renal tissue and zofenopril prevented this IR injury.
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PMID:An Angiotensin-converting enzyme inhibitor, zofenopril, prevents renal ischemia/reperfusion injury in rats. 1695 Dec 75


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