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)

Sexual dimorphisms of atherosclerosis and the susceptibility to arrhythmias and antiarrhythmic treatment have been reported. This study investigated acute effects of amiodarone on endothelium-dependent relaxation in the aorta of male and female apoE0 mice with advanced atherosclerosis. Amiodarone tissue uptake was quantified by high-performance liquid chromatography, and xanthine oxidase-dependent superoxide anion formation was investigated in vitro in presence or absence of amiodarone. Incubation with amiodarone for 30 min improved endothelium-dependent relaxation, which was associated with rapid vascular accumulation of amiodarone (P < 0.001) that was sex-dependent. In males, reduced endothelium-dependent relaxation was improved by amiodarone (from 88 +/- 3% to 100 +/- 2%, P < 0.01). Spontaneous phasic contractions, which were greater in females than in males (P < 0.001), were completely abolished by amiodarone (P < 0.0001). Amiodarone also inhibited generation of superoxide anion (P < 0.0001). These data show that amiodarone rapidly accumulates in atherosclerotic vascular tissue, abolishes vascular autorhythmicity, and improves endothelium-dependent function in atherosclerotic arteries. Antioxidant and vasodilator effects following amiodarone administration may contribute to its antiarrhythmic effects.
J Cardiovasc Pharmacol 2007 Nov
PMID:Antioxidant activity and sex differences of acute vascular effects of amiodarone in advanced atherosclerosis. 1803 69

The recognition that uric acid plays a significant role in cardiac function has been slow to be appreciated. About 50 years ago it was recognized that gout and high uric acid levels were often a marker for coronary heart disease, Since then the literature has contained several hundred studies which have demonstrated a great deal of the physiology of xanthine oxidase inhibition. A reduction in xanthine oxidase improves cardiac output, improves endothelial function, reduces myocardial infarct size, reduces inflammation, reduces myocardial oxidative stress and platelet adhesiveness. It seems logical that these effects would be beneficial to patients with congestive heart failure. A large placebo controlled trial with Allopurinol seems very likely to demonstrate that this old fashioned drug provides a new found benefit.
Cardiovasc Hematol Disord Drug Targets 2007 Dec
PMID:Xanthine oxidase inhibitors the unappreciated treatment for heart failure. 1822 Jul 28

Oxidative stress is a common denominator in many aspects of the pathogenesis of atherosclerosis and cardiovascular diseases. Some drugs, such as vitamin C, vitamin E, and a free radical scavenger, edaravone, are prescribed with oxidative stress as their main target. Furthermore, of the drugs in current clinical use, such as anti-hypertension reagents including angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB), and anti-hyperlipidemic reagents like statins, protect various organs, e.g., vessel, brain, heart, and kidney, via anti-oxidative stress effects in addition to their original pharmacological properties. While results of clinical trials of anti-oxidative stress reagents in patients with cardiovascular disease are contradictory to date, this may be explained by a variety of reasons such as an inadequate study design. More competent anti-oxidative reagents are awaited, and superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H oxidase inhibitors, which regulate intracellular redox reaction and subsequently inhibit oxidative stress, are among promising candidates of future drug developments currently receiving much interest. In this review, the current advances will be highlighted in development of novel anti-oxidative therapeutic approaches against cardiovascular diseases.
Recent Pat Cardiovasc Drug Discov 2006 Jun
PMID:Oxidative stress in cardiovascular disease: a new avenue toward future therapeutic approaches. 1822 Oct 82

Endothelial cells control vascular homeostasis by generating paracrine factors that regulate vascular tone, inhibit platelet function, prevent adhesion of leukocytes, and limit proliferation of vascular smooth muscle. The dominant factor responsible for many of those effects is endothelium-derived nitric oxide (NO). Endothelial dysfunction characterized by enhanced inactivation or reduced synthesis of NO, alone or in combination, is seen in conjunction with risk factors for cardiovascular disease. Endothelial dysfunction can promote vasospasm, thrombosis, vascular inflammation, and proliferation of the intima. Vascular oxidative stress and increased production of reactive oxygen species contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase or the mitochondrial respiratory chain) and antioxidant enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase and paraoxonase). In addition, small-molecular-weight antioxidants might have a role in the defense against oxidative stress. Increased concentrations of reactive oxygen species reduce bioactive NO through chemical inactivation, forming toxic peroxynitrite, which in turn can uncouple endothelial NO synthase to form a dysfunctional superoxide-generating enzyme that contributes further to oxidative stress. The role of oxidative stress in vascular dysfunction and atherogenesis, and strategies for its prevention are discussed.
Nat Clin Pract Cardiovasc Med 2008 Jun
PMID:Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. 1846 Oct 48

Many studies have shown a strong correlation between urate levels and cardiovascular disease. The formation of urate is complex as the same enzyme that produces urate, xanthine oxidase (XO) also catalyzes the formation of reactive oxygen species (ROS). There is some evidence that the urate molecule has free radical scavenging properties in vitro and acute infusions of urate improve endothelial function in at-risk populations. High levels of ROS are clearly linked to worse outcome in a variety of conditions. Allopurinol has been the archetypal XO inhibitor for over 40 years. Small studies have demonstrated its beneficial effects, mainly in heart failure but also in a variety of other cohorts of patients with cardiovascular risk. It is a safe agent, provided suitable patients are chosen and monitored carefully. Newer promising agents like oxypurinol have not shown the expected benefits in larger multicentered studies. This review looks at the biology of urate, its role in cardiovascular disease, the possible mechanisms by which XO inhibitors exert their beneficial effect on endothelial dysfunction, and examines the possible causes for the failure of newer agents to live up to expectations.
Cardiovasc Ther 2008
PMID:The role of urate and xanthine oxidase inhibitors in cardiovascular disease. 1846 21

Sulforaphane, a cruciferous isothiocyanate compound, upregulates cytoprotective genes in liver, but its effects on antioxidants and phase 2 defenses in vascular cells are unknown. Here we report that incubation of rat aortic smooth muscle A10 cells with sulforaphane (0.25-5 microM) resulted in concentration-dependent induction of a spectrum of important cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, the reduced form of glutathione (GSH), glutathione peroxidase, glutathione reductase (GR), glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1). Sulforaphane also increased levels/activities of SOD, catalase, GSH and GST in isolated mitochondria of aortic smooth muscle cells. Time-dependent sulforaphane-induced increases in the mRNA levels for MnSOD, catalase, the catalytic subunit of gamma-glutamylcysteine ligase, GR, GST-A1, GST-P1, and NQO1 were observed. Pretreatment with sulforaphane (0.5, 1, and 5 microM) protected aortic smooth muscle cells from oxidative and electrophilic cytotoxicity induced by xanthine oxidase (XO)/xanthine, H2O2, SIN-1-derived peroxynitrite, 4-hydroxy-2-nonenal, and acrolein. Furthermore, sulforaphane pretreatment prevented intracellular accumulation of reactive oxygen species (ROS) after exposure of the cells to XO/xanthine, H2O2, or SIN-1. Taken together, this study demonstrates that in the aortic smooth muscle cells sulforaphane at physiologically relevant concentrations potently induces a series of total cellular as well as mitochondrial antioxidants and phase 2 enzymes, which is accompanied by dramatically increased resistance of these vascular cells to oxidative and electrophilic stress.
Cardiovasc Toxicol 2008
PMID:Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress. 1860 71

The endothelium synthesizes and releases several vasodilator substances, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in animals and humans and that superoxide anions derived from endothelial nitric oxide synthases (NOSs) system are an important precursor for EDHF/H2O2 in mice. There are several intracellular sources of superoxide anions other than NOSs, including NAD(P)H oxidase, xanthine oxidase, lipoxygenase, and mitochondrial electron transport chain. In this study, we examined the possible role of endothelial oxidases other than NOSs in the EDHF-mediated responses. In angiotensin II-infused mice, both EDHF-mediated relaxations and hyperpolarizations to acetylcholine were significantly reduced, nitric oxide-mediated relaxations were rather enhanced, and vascular smooth muscle responses were preserved. Antihypertensive treatment normalized blood pressure but failed to improve EDHF-mediated responses in those mice. Acute inhibition of endothelial oxidases other than NOSs, including NAD(P)H oxidase, xanthine oxidase, lipoxygenase, or mitochondrial electron transport chain, had no inhibitory effects on EDHF-mediated responses. Furthermore, in p47phox-knockout mice, EDHF-mediated responses were unaltered. These results suggest that endothelial oxidases other than NOSs are not involved in EDHF/H2O2 responses in mice, suggesting a specific link between endothelial NOSs system and EDHF responses under physiological conditions.
J Cardiovasc Pharmacol 2008 Dec
PMID:Roles of endothelial oxidases in endothelium-derived hyperpolarizing factor responses in mice. 1903 34

The importance of xanthine oxidase and its products is being increasingly recognized in cardiovascular medicine. Patients who have had a stroke are at high risk of future cardiovascular events and this risk is higher in those with high urate levels. The aim of this pilot study was to see if inhibiting xanthine oxidase altered arterial wave reflection, determined from the augmentation index (AIx). In a double-blind study, 30 patients with high urate (> or = 0.38 mmol/L) were randomized to 300 mg allopurinol or placebo for 8 weeks. AIx measurements were made before and after treatment using the validated SphygmoCor pulse waveform analysis system. For patients treated with allopurinol, there was a reduction in AIx from 26.08 +/- 3.31% to 20.15 +/- 2.23% compared with an increase in the placebo group from 23.57 +/- 3.13% to 27.64 +/- 3.44% (P = 0.031, ANOVA). The vascular benefits of allopurinol are rapidly emerging. We have demonstrated that allopurinol has beneficial effects on AIx, a validated measure of vascular function. A further larger study is warranted to look at whether a therapeutic intervention with allopurinol will impact positively on mortality and morbidity in stroke survivors.
Cardiovasc Ther 2008
PMID:Allopurinol treatment reduces arterial wave reflection in stroke survivors. 1903 75

Hypertension reigns as a leading cause of cardiovascular morbidity and mortality worldwide. Excessive reactive oxygen species (ROS) have emerged as a central common pathway by which disparate influences may induce and exacerbate hypertension. Potential sources of excessive ROS in hypertension include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mitochondria, xanthine oxidase, endothelium-derived NO synthase, cyclooxygenase 1 and 2, cytochrome P450 epoxygenase, and transition metals. While a significant body of epidemiological and clinical data suggests that antioxidant-rich diets reduce blood pressure and cardiovascular risk, randomized trials and population studies using natural antioxidants have yielded disappointing results. The reasons behind this lack of efficacy are not completely clear, but likely include a combination of (1) ineffective dosing regimens, (2) the potential pro-oxidant capacity of some of these agents, (3) selection of subjects less likely to benefit from antioxidant therapy (too healthy or too sick), and (4) inefficiency of nonspecific quenching of prevalent ROS versus prevention of excessive ROS production. Commonly used antioxidants include Vitamins A, C and E, L-arginine, flavanoids, and mitochondria-targeted agents (Coenzyme Q10, acetyl-L-carnitine, and alpha-lipoic acid). Various reasons, including incomplete knowledge of the mechanisms of action of these agents, lack of target specificity, and potential interindividual differences in therapeutic efficacy preclude us from recommending any specific natural antioxidant for antihypertensive therapy at this time. This review focuses on recent literature evaluating naturally occurring antioxidants with respect to their impact on hypertension.
Cardiovasc Ther 2010 Aug
PMID:Natural antioxidants and hypertension: promise and challenges. 2037 Jul 91

Vascular disease in hypertension and diabetes is associated with increased oxidants. The oxidants arise from NADPH oxidase, xanthine oxidase, and mitochondria. Superoxide anion and hydrogen peroxide are produced by both leukocytes and vascular cells. Nitric oxide is produced in excess by inducible nitric oxide synthase, and the potent oxidant, peroxynitrite, is formed from superoxide and nitric oxide. The damage to proteins caused by oxidants is selective, affecting specific oxidant-sensitive amino acid residues. With some important vascular proteins, for example, endothelial nitric oxide synthase, prostacycline synthase, and superoxide dismutase, oxidation of a single susceptible amino acid inactivates the enzyme. The beneficial effects of antioxidants, at least in animal models of hypertension and diabetes, can in part be ascribed to protection of these and other proteins. Mutant proteins lacking their reactive constituent can recapitulate some disease phenotypes suggesting a pathogenic role of the oxidation. Thus, many of the shared functional abnormalities of hypertensive and diabetic blood vessels may be caused by oxidants. Although studies using antioxidants have failed in patients, the successful treatment of vascular disease with HMG-CoA reductase inhibitors, thromboxane A2 antagonists, and polyphenols may depend on their anti-inflammatory effects and ability to decrease production of damaging oxidants.
J Cardiovasc Pharmacol 2010 Apr
PMID:Vascular oxidative stress: the common link in hypertensive and diabetic vascular disease. 2042 35


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