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: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic heart failure is characterized by increased vascular systemic resistances secondary to activation of various vasoconstrictor systems and to decreased endothelium-dependent vasodilatation. Endothelial dysfunction, described both in animals and in humans, may be caused by an increased inactivation of nitric oxide (NO) by reactive oxygen species, leading to decreased NO bioavailability and impaired vasodilatation. Increased levels of free radicals in heart failure may result either from increased production or a decrease in the cellular antioxidant reserves. Free radicals are produced by three enzymatic systems: NADH/NADPH oxidase (after stimulation by angiotensin II or TNF-alpha), xanthine oxidase or endothelial NO-synthase (NOS) itself. However, oxidative stress alone cannot explain endothelial dysfunction. Other mechanisms involved in the regulation of the production of NO (e.g. decreased expression and/or activity of the NOS) and/or changes in production of vasoconstrictors may participate in this impaired endothelium-dependent vasodilatation in heart failure.
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PMID:[Oxidative stress and endothelial dysfunction in heart failure]. 1180 96

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.
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PMID:Clinical aspects of reactive oxygen and nitrogen species. 1577 17

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species (ROS), such as the superoxide radical, and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include the NAD(P)H oxidase, the xanthine oxidase, and mitochondrial superoxide-producing enzymes. Superoxide produced by the NADPH oxidase may react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, thereby switching an antiatherosclerotic NO-producing enzyme to an enzyme that may initiate or even accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and has also been demonstrated to occur within the smooth muscle cell layer in the setting of hypercholesterolemia, diabetes mellitus, hypertension, congestive heart failure, and nitrate tolerance. Increased superoxide production by the endothelial and/or smooth muscle cells has important consequences with respect to signaling by the soluble guanylyl cyclase (sGC) and the cGMP-dependent protein kinase I (cGK-I), the activity and expression of which has been shown to be regulated in a redox-sensitive fashion. The present review summarizes current concepts concerning eNOS uncoupling and also focuses on the consequences for downstream signaling with respect to activity and expression of the sGC and cGK-I in various diseases.
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PMID:Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. 1587 5

Endothelial dysfunction/activation underlies the development of long-term cardiovascular complications and atherosclerosis. The aim of this study was to examine a direct role for exogenous sublethal flux of superoxide on endothelial cell dysfunction. Human umbilical vein endothelial cells (HUVEC) were exposed to superoxide generated by 0.1 mM xanthine and 4 mU/ml xanthine oxidase for 15 min and essential endothelial functions were examined. Superoxide dismutase and/or catalase was used as scavenger for O(2)(-)/H(2)O(2) to determine the key culprit. HUVEC detachment was determined by neutral red uptake and apoptosis by annexin V binding. Inflammation was estimated by IL-8 mRNA expression and cellular adhesion molecules (CAM). eNOS and iNOS message and eNOS protein served as an indirect measure for NO. Procoagulable state was evaluated by estimating the intracellular tissue factor. Activation of endothelial NADPH oxidase was determined by lucigenin chemiluminescence. Sublethal superoxide dose evoked: (1) proinflammatory state manifested by increased IL-8 mRNA expression and CAM on the endothelial surface, (2) HUVEC apoptosis and activated endothelial NADPH oxidase, (3) increase in intracellular tissue factor, and (4) decrease in eNOS mRNA and protein and up-regulation of iNOS mRNA. We conclude that extracellular low flux of superoxide exhibits pleiotropic characteristics, triggering activation/dysfunction of endothelial cells.
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PMID:Exogenous superoxide mediates pro-oxidative, proinflammatory, and procoagulatory changes in primary endothelial cell cultures. 1621 39

Endothelial dysfunction (ED) is an early feature of cardiovascular risk and diabetes. Hyperglycemia and hyperlipidemia are causative factors. Excessive endothelial mitochondrial superoxide (ROS) production with hyperglycemia and hyperlipidemia is a key mechanism. Inositol components of an insulin inositol glycan mediator, d-chiro-inositol (DCI) and 3-O-methyl DCI (pinitol), decrease hyperglycemia and hyperlipidemia. We tested whether these, myoinositol and dibutyryl DCI (db-DCI), would prevent or reverse ED in diabetic rats and rabbits. Oral inositols reduced hyperglycemia and hypertriglyceridemia with different potencies and prevented ED in rat aortic rings and mesenteric beds. Inositols added in vitro to five diabetic tissues reversed ED. Relaxation by Ach, NO, and electrical field stimulation was potentiated by inositols in vitro in rabbit penile corpus cavernosa. Inositols in vitro restored impaired contraction by the eNOS inhibitor l-NAME and increased NO effectiveness. DCI and db-DCI decreased elevated ROS in endothelial cells in high glucose and db-DCI reduced PKC activation, hexosamine pathway activity, and advanced glycation end products to basal levels. Xanthine/xanthine oxidase generated superoxide was reduced by superoxide dismutase or inositols, with db-DCI efficacious in a mechanism requiring chelated Fe(3+). Histochemical examination of rat aortic rings for protein SNO demonstrated a decrease in diabetic rings with restoration by inositols. In summary, inositols prevented and reversed ED in rat and rabbit vessels, reduced elevated ROS in endothelial cells, potentiated nitrergic or vasculo-myogenic relaxations, and preserved NO signaling. These effects are related to their metabolic actions, direct superoxide scavenging, and enhancing and protecting NO signaling. Of the inositols tested, db-DCI was most effective.
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PMID:Inositols prevent and reverse endothelial dysfunction in diabetic rat and rabbit vasculature metabolically and by scavenging superoxide. 1637 99

Endothelial dysfunction in the setting of cardiovascular risk factors such as hypercholesterolemia, diabetes mellitus, chronic smoking, as well hypertension, is, at least in part, dependent of the production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO). ROS-producing enzymes involved in increased oxidative stress within vascular tissue include NADPH oxidase, xanthine oxidase, and mitochondrial superoxide producing enzymes. Superoxide produced by the NADPH oxidase may react with NO, thereby stimulating the production of the NO/superoxide reaction product peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, therefore switching an antiatherosclerotic NO producing enzyme to an enzyme that may accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and also occurs within the smooth muscle cell layer. Increased superoxide production has important consequences with respect to signaling by the soluble guanylate cyclase and the cGMP-dependent kinase I, which activity and expression is regulated in a redox-sensitive fashion. The present review will summarize current concepts concerning eNOS uncoupling, with special focus on the role of tetrahydrobiopterin in mediating eNOS uncoupling.
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PMID:Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. 1832 Dec 9

Endothelial dysfunction (ED) in the setting of cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes mellitus, chronic smoking as well as in patients with heart failure has been shown to be at least in part dependent on the production of reactive oxygen species (ROS) such as superoxide and the subsequent decrease in vascular bioavailability of nitric oxide (NO). Methods to quantify endothelial dysfunction include forearm plethysmography, flow-dependent dilation of the brachial artery, finger-pulse plethysmography, pulse curve analysis, and quantitative coronary angiography after intracoronary administration of the endothelium-dependent vasodilator acetylcholine. Superoxide sources include the NADPH oxidase, xanthine oxidase, and mitochondria. Superoxide produced by the NADPH oxidase may react with NO released by the endothelial nitric oxide synthase (eNOS) thereby generating peroxynitrite (ONOO-), leading to eNOS uncoupling and therefore eNOS-mediated superoxide production. The present review will discuss current concepts of how to assess endothelial function, prognostic implications of ED, mechanisms underlying ED with focus on oxidative stress and circulating biomarkers, which have been proposed to indicate endothelial dysfunction and/or damage, respectively.
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PMID:Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. 1838 84

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.
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PMID:Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. 1846 Oct 48

Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of cardiovascular diseases (CVD), and in particular atherosclerosis. These ROS are released from different sources, such as xanthine oxidase, lipoxygenase, nicotinamide adenine dinucleotide phosphate oxidase, the uncoupling of nitric oxide synthase and, in particular, mitochondria. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not clear, oxidative stress seems to play an important role. In general, ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. This review considers the process of atherosclerosis from a mitochondrial perspective, and assesses strategies for the targeted delivery of antioxidants to mitochondria that are currently under development. We will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for atherosclerosis.
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PMID:Oxidative stress and mitochondrial dysfunction in atherosclerosis: mitochondria-targeted antioxidants as potential therapy. 1990 43

Endothelial dysfunction is associated with KCa3.1 dysfunction and contributes to the development of hypertension in preeclampsia. However, evidence of endothelial KCa3.1 dysfunction in the vascular system from women with preeclampsia is still lacking. Therefore, we examined whether endothelial KCa3.1 dysfunction occurs in vessels from women with preeclampsia. We compared KCa3.1 and NADPH oxidase (NOX) expression in umbilical vessels and primary cultured human umbilical vein endothelial cells (HUVECs) from normal (NP; n=17) and preeclamptic pregnancy (PE; n=19) and examined the effects of plasma from NP or PE on KCa3.1 and NOX2 expression in primary cultured HUVECs from NP or human uterine microvascular endothelial cells. The endothelial KCa3.1 was downregulated, and NOX2 was upregulated, in umbilical vessels and HUVECs from PE, compared with those from NP. In addition, HUVECs from PE showed a significant decrease in KCa3.1 current. Plasma from PE induced KCa3.1 down regulation, NOX2 upregulation, phosphorylated-p38 mitogen-activated protein kinase downregulation, and superoxide generation, and these effects were prevented by antioxidants (tempol or tiron), NOX2 inhibition, or anti-lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) antibody. Oxidized LDL and the superoxide donor xanthine/xanthine oxidase mixture induced KCa3.1 downregulation. In contrast, plasma from PE did not generate hydrogen peroxide, and the hydrogen peroxide donor tert-butylhydroperoxide induced KCa3.1 upregulation. These results provide the first evidence that plasma from PE generates superoxide via a LOX1-NOX2-mediated pathway and downregulates endothelial KCa3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia. This suggests KCa3.1as a novel target for patients with preeclampsia.
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PMID:NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia. 2326 40


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