Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org.
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PMID:Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. 1080 76

Both cardiovascular diseases such as hypertension and atherosclerosis and metabolic disorders such as diabetes mellitus and hyperlipidemia are closely related with obesity. In recent studies, superoxide is supposed to play an important role in pathogenesis of the cardiovascular diseases. Superoxide inhibits the biological action of nitric oxide, known as endothelium-derived relaxing factor, leading to vasoconstriction. Moreover, superoxide directly affects the functions of endothelial cells and vascular smooth muscle cells. It has been investigated that the metabolic disorders associated with obesity enhance the superoxide production in the arterial walls through the insulin resistance. In hyperglycemic state, the production of superoxide is stimulated and the superoxide dimustase is inhibited by non-enzymatic glycation, known as Maillard reaction. Hyperlipidemia also increases endothelial superoxide production. Superoxide may act a key role in relationship between the cardiovascular diseases and the metabolic disorders associated with obesity.
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PMID:[The role of superoxide in relationship between the cardiovascular diseases and the metabolic disorders associated with obesity]. 1094 18

Vascular disease and vasomotor responses are largely influenced by oxidant stress. Superoxide is generated via the cellular oxidase systems, xanthine oxidase, and NADH/NADPH oxidases. Once formed, superoxides participate in a number of reactions, yielding various free radicals such as hydrogen peroxide, peroxynitrite, oxidized low-density lipoprotein, or hypochlorous acid. Numerous cellular antioxidant systems exist to defend against oxidant stress; glutathione and the enzymes superoxide dismutase and glutathione peroxidase are critical for maintaining the redox balance of the cell. However, the redox state is disrupted by certain vascular diseases. It appears that oxidant stress both promotes and is induced by diseases such as hypertension, atherosclerosis, and restenosis as well as by certain risk factors for coronary artery disease including hyperlipidemia, diabetes, and cigarette smoking. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, namely adverse vessel reactivity, vascular smooth muscle cell proliferation, macrophage adhesion, platelet activation, and lipid peroxidation.
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PMID:Oxidant stress in the vasculature. 1112 5

-Oxygen free radicals are believed to play a key role in cellular proliferation, and increased concentrations of these molecules have been implicated in the pathogenesis of endothelial dysfunction in diabetes mellitus. Our aim was to study the role of superoxide anions in endothelial cell proliferation under conditions of normoglycemia and hyperglycemia. Human aortic endothelial cells (HAECs) and human umbilical vein endothelial cells (HUVECs) exposed to adenoviral vectors encoding CuZnSOD (AdCuZnSOD), ss-galactosidase (Adssgal), or diluent (control) were cultured in normal glucose (NG, 5.5 mmol/L) or high glucose (HG, 28 mmol/L) medium. Cell proliferation was compared by use of [(3)H]thymidine incorporation and cell count in transduced and control cells in the setting of NG and HG. Transgene expression was detected in transduced cells by X-gal staining and by Western analysis and SOD activity assay in AdCuZnSOD-transduced cells. Superoxide production was significantly (P:<0.05) decreased in AdCuZnSOD-transduced cells cultured in both NG and HG medium. In NG, AdCuZnSOD-transduced endothelial cells had decreased proliferation compared with control cells. After 48 hours in HG, superoxide levels were increased and DNA synthesis was decreased (P:<0.05) in control and Adssgal-transduced but were not affected in AdCuZnSOD-transduced cells. In addition, after 7 days in HG, cell counts were reduced (P:<0.05) in control (73+/-2.5%) and Adssgal-transduced (75+/-3.4%) but not in AdCuZnSOD-transduced cells (89+/-3.4%). These results suggest that either a deficiency or an excess of superoxide anions inhibits endothelial cell proliferation, and the inhibitory effect of increased superoxide due to hyperglycemia can be reversed by CuZnSOD overexpression.
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PMID:Superoxide anions and endothelial cell proliferation in normoglycemia and hyperglycemia. 1115 52

Vitamin B(6) (pyridoxine) supplementation has been found beneficial in preventing diabetic neuropathy and retinopathy, and the glycosylation of proteins. Oxygen radicals and oxidative damage have been implicated in the cellular dysfunction and complications of diabetes. This study was undertaken to test the hypothesis that pyridoxine (P) and pyridoxamine (PM) inhibit superoxide radical production, reduce lipid peroxidation and glycosylation, and increase the (Na+ + K+)-ATPase activity in high glucose-exposed red blood cells (RBC). Superoxide radical production was assessed by the reduction of cytochrome C by glucose in the presence and absence of P or PM in a cell-free buffered solution. To examine cellular effects, washed normal human RBC were treated with control and high glucose concentrations with and without P or PM. Both P and PM significantly lowered lipid peroxidation and glycated hemoglobin (HbA(1)) formation in high glucose-exposed RBC. P and PM significantly prevented the reduction in (Na+ + K+)-ATPase activity in high glucose-treated RBC. Thus, P or PM can inhibit oxygen radical production, which in turn prevents the lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction induced by the hyperglycemia. This study describes a new biochemical mechanism by which P or PM supplementation may delay or inhibit the development of complications in diabetes.
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PMID:Pyridoxine and pyridoxamine inhibits superoxide radicals and prevents lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction in high glucose-treated human erythrocytes. 1116 69

Increased production of oxygen free radicals is an important mechanism of endothelial dysfunction in diabetes mellitus. Our goal was to test whether adenovirus (Ad)-mediated gene transfer of copper/zinc (CuZn) or manganese superoxide dismutase (Mn SOD) improves relaxation of diabetic vessels. The aortas from 9 alloxan-induced diabetic mellitus (DM) and 16 control rabbits were used. Control and DM rings were transduced ex vivo with Ad vectors encoding Mn SOD (AdMn SOD), CuZn SOD (AdCuZn SOD), beta-galactosidase (Ad(beta)gal), or diluents. In the absence of gene transfer, SOD activity was significantly increased in DM aortas. Transgene expression in DM AdCuZn SOD and DM AdMn SOD-transduced vessels was confirmed by Western blot analysis and by increased SOD activity (DM AdCuZn SOD, 76.2 +/- 9.3; DM AdMn SOD, 65.2 +/- 4.8; P < 0.05 vs. DM Ad(beta)gal; 50.9 +/- 4.4 U/mg protein). Superoxide production was increased in DM Ad(beta)gal-transduced aorta and relaxations to acetylcholine were impaired in these vessels. Gene transfer of CuZn SOD and Mn SOD corrected both of these defects. Thus Ad-mediated gene transfer CuZn and Mn SOD to the diabetic aorta improves endothelium-dependent relaxation.
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PMID:Gene transfer of superoxide dismutase isoforms reverses endothelial dysfunction in diabetic rabbit aorta. 1135 6

Experiments were performed to test the hypothesis that diabetes mellitus disrupts the balance between synthesis and degradation of nitric oxide (NO) in the renal cortex. Diabetes was induced by injection of streptozotocin, and sufficient insulin was provided to maintain moderate hyperglycemia for the ensuing 2 wk. Despite an 80% increase in total NO synthase activity measured by L-citrulline assay, nicotinamide adenine dinucleotide phosphate-diaphorase staining was unaltered, and no changes in NO synthase isoform protein levels or their distribution were evident in renal cortex from diabetic rats. Superoxide anion production was accelerated twofold in renal cortical slices from diabetic rats, with an associated 50% increase in superoxide dismutase activity. Western blots prepared by use of a monoclonal antinitrotyrosine antibody revealed an approximately 70-kD protein in renal cortex from sham rats, the nitrotyrosine content of which was threefold greater in cortical samples from diabetic rats. These observations indicate that the early stage of diabetes mellitus provokes accelerated renal cortical superoxide anion production in a setting of normal or increased NO production. This situation can be expected to promote peroxynitrite formation, resulting in the tyrosine nitration of a single protein of unknown identity, as well as a decline in the bioavailability of NO. These events are consistent with the postulate that oxidative stress promotes NO degradation in the renal cortex during the early stage of diabetes mellitus.
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PMID:Nitric oxide synthesis and oxidative stress in the renal cortex of rats with diabetes mellitus. 1146 35

Bed rest is an integral part of treatment of numerous diseases. Typical examples are bone fractures of lower extremities and pelvis. Temporary immobilization is necessary also, e.g., in heart diseases (stroke), backbone and imminent abortion. The sick organism spares energy during the bed rest wich is beneficial. However, bed rest results in many alterations which are disadavantageous. They concern the function of almost all organs and systems but affect most significantly the locomotor and ciruclatory systems. Bed rest brings also about changes in the composition of peripheral blood and functions of the morphotic elements of blood. Red blood cells are subjected to the action of large amounts of reactive oxygen species (ROS). During oxidation of hemoglobin to methemoglobin superoxide radical anion (O2-) is formed: HbFe2+ + O2 --> MetHbFe3+ + O2- (1) Ferrous and ferric ions present in the cytoplasm of red blood cells may be catalysts of the Fenton reaction leading to the production of the hydroxyl radical: O2- + Fe3+ --> O2- + Fe2+ (2) Fe2+ + H2O2 --> Fe3+ + OH + HO- (3) OH shows a tremendous reactivity. It may react with lipids, proteins, nucleic acids and carbohydrates. The process of lipid peroxidation is best understood. It concerns mainly polyunsaturated fatty acids present in cell membranes. Peroxidation of membrane lipids decreases membrane fluidity and impairs its barrier function. The lowered membrane fluidity compromises erythrocyte deormability which in turn disturbs oxygen delivery to the tissues. End productions of lipid peroxidation are low-molecular wieght compounds, among them carbohydrates (ethane and pentane) and aldehydes, e.g. malondialdehyde (MDA). MDA concentration is an acknowldeged marker of the intensity of lipid peroxidation. Erythrocytes contain a complex system of protection against the action of ROS. It includes various enzymatic and non-enzymatic mechanism. The most important antioxidative enzymes of the red blood cells are superoxide dismutase (Cu,Zn-SOD, EC 1.15.1.1) catalase (CAT, EC 1.11.1.6) and glutathione peroxidase (GSH-Px, EC 1.11.1.9). Cu,Zn-SOD catalyzes the dismuation of O2- to hydrogen peroxide (H2O2). Catalase and peroxidase remove H2O2 and, moreover, GSH-Px can reduce lipid peroxides. Under normal conditions an equilibrium exists between the formation and removal ROS. If ROS are formed in excess or the defensive antioxidative mechanism are inefficient, oxidative stress develops. Derangement of the equilibrium between the formation and removal of ROS is important in the pathosgenesis of many diseases, e.g. atherosclerosis, diabetes, Down syndrome and Alzheimer disease. There are literature data on disturbances of enzymatic antioxidant defense mechanism of blood plateless during bed rest. This study was aimed at an examination of the post-traumatic bed rest on the enzymatic antioxidative defense mechanisms and lipid peroxidation in erythrocytes.
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PMID:Effect of long term bed rest in men on enzymatic antioxidative defence and lipid peroxidation in erythrocytes. 1154 39

Aminoacetone (AA) is a threonine and glycine catabolite long known to accumulate in cri-du-chat and threoninemia syndromes and, more recently, implicated as a contributing source of methylglyoxal (MG) in diabetes mellitus. Oxidation of AA to MG, NH(4)(+), and H(2)O(2) has been reported to be catalyzed by a copper-dependent semicarbazide sensitive amine oxidase (SSAO) as well as by Cu(II) ions. We here study the mechanism of AA aerobic oxidation, in the presence and absence of iron ions, and coupled to iron release from ferritin. Aminoacetone (1-7 mM) autoxidizes in Chelex-treated phosphate buffer (pH 7.4) to yield stoichiometric amounts of MG and NH(4)(+). Superoxide radical was shown to propagate this reaction as indicated by strong inhibition of oxygen uptake by superoxide dismutase (SOD) (1-50 units/mL; up to 90%) or semicarbazide (0.5-5 mM; up to 80%) and by EPR spin trapping studies with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), which detected the formation of the DMPO-(*)OH adduct as a decomposition product from the DMPO-O(2)(*)(-) adduct. Accordingly, oxygen uptake by AA is accelerated upon addition of xanthine/xanthine oxidase, a well-known enzymatic source of O(2)(*)(-) radicals. Under Fe(II)EDTA catalysis, SOD (<50 units/mL) had little effect on the oxygen uptake curve or on the EPR spectrum of AA/DMPO, which shows intense signals of the DMPO-(*)OH adduct and of a secondary carbon-centered DMPO adduct, attributable to the AA(*) enoyl radical. In the presence of iron, simultaneous (two) electron transfer from both Fe(II) and AA to O(2), leading directly to H(2)O(2) generation followed by the Fenton reaction is thought to take place. Aminoacetone was also found to induce dose-dependent Fe(II) release from horse spleen ferritin, putatively mediated by both O(2)(*)(-) and AA(*) enoyl radicals, and the co-oxidation of added hemoglobin and myoglobin, which may be viewed as the initial step for potential further iron release. It is thus tempting to propose that AA, accumulated in the blood and other tissues of diabetics, besides being metabolized by SSAO, may release iron and undergo spontaneous and iron-catalyzed oxidation with production of reactive H(2)O(2) and O(2)(*)(-), triggering pathological responses. It is noteworthy that noninsulin-dependent diabetes has been frequently associated with iron overload and oxidative stress.
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PMID:Aerobic oxidation of aminoacetone, a threonine catabolite: iron catalysis and coupled iron release from ferritin. 1155 49

Superoxide anion can modulate vascular smooth muscle tone and is potentially involved in diabetic vascular complications. The present study was undertaken to characterize both vascular production and the enzymatic source of superoxide anion in type 2 diabetic rats. In the thoracic aorta of OLETF rats, endothelium-dependent relaxation was markedly attenuated compared with that of control (LETO) rats in association with a significant increase in superoxide production (2,421.39 +/- 407.01 nmol x min(-1) x mg(-1)). The increased production of superoxide anion was significantly attenuated by diphenyleneiodonium (DPI; 10 micromol/l), an inhibitor of NAD(P)H oxidase. The production of superoxide anion in response to NADH as a substrate was markedly increased in the vascular homogenates, but NADPH, arachidonic acid, xanthine, and succinate produced only small increases in chemiluminescence. In line with these results, studies using various enzyme inhibitors, such as DPI, allopurinol, rotenone, N(G)-monomethyl-L-arginine, and indomethacin, suggest that the predominant source of superoxide anion in vascular particulate fraction is NADH-dependent membrane-bound oxidase. Furthermore, the expression of p22phox, a major component of vascular NAD(P)H oxidase, was markedly increased in the aorta from OLETF rats compared with that of LETO rats. These findings suggest that upregulated expression of p22phox mRNA and enhanced NADH oxidase activity contribute to the impaired endothelium-dependent vasodilation in OLETF rats.
Diabetes 2002 Feb
PMID:Vascular NADH oxidase is involved in impaired endothelium-dependent vasodilation in OLETF rats, a model of type 2 diabetes. 1181 64


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