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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We characterized a novel form of extracellular superoxide dismutase (ecSOD) in atherosclerotic vessels. Specific activity and protein expression of ecSOD was increased two- to threefold in apo E-deficient compared with control aortas. RNase protection assays demonstrated that the expected ecSOD transcript was not increased in either apo E-deficient mice or cholesterol-fed LDL receptor-deficient mice, but that a second, lower molecular weight transcript was present and became predominant as atherosclerosis progressed. Sequence analysis revealed that this novel ecSOD has a 10-bp deletion in the 3' untranslated region and an asparagine to aspartic acid mutation at amino acid 21. Studies of isolated macrophages and immunohistochemistry suggested that the truncated ecSOD transcript was expressed by lipid-laden but not control macrophages. Recombinant wild-type and novel ecSODs expressed in Sf9 cells exhibited similar SOD activities. These experiments show that ecSOD expression is increased in atherosclerotic vessels and that this is characterized by an alteration in mRNA and protein structure. Further, the source of this altered ecSOD is likely the lipid-laden macrophage. The enzymatic properties of this novel ecSOD may have important implications for the function of the lipid-laden macrophage and the atherosclerotic process.
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PMID:Vascular expression of extracellular superoxide dismutase in atherosclerosis. 959 66

Modest elevations of circulating homocysteine are common in patients with vascular disease. We explored interrelations between total plasma homocysteine levels and mutations in genes for three key enzymes in methionine-homocysteine metabolism. Methyltetrahydrofolate reductase (MTHFR) 677C-->T, cystathionine beta synthase (CBS) 68-bp insertion at exon 8, and methionine synthase (MS) 2756A-->G were typed in 685 Australian caucasian patients aged < or =65 years with and without angiographically documented coronary artery disease (CAD). We also assessed associations between homocysteine levels and extracellular superoxide dismutase (EC-SOD) and other CAD risk factors. There were significant correlations between plasma total homocysteine, and EC-SOD (r = 0.170, p = 0.001 for men; r = 0.241, p = 0.003 for women) and LDL (r = 0.153, p = 0.001 for men; r = 0.132, p = 0.081 for women). Levels were also significantly higher among patients with unstable angina (15.30+/-0.44 micromol/l for men, 14.44+/-0.74 micromol/l for women) than those without angina (13.98+/-0.38 micromol/l for men, 13.41+/-0.98 micromol/l for women) or with stable angina (14.00+/-0.37 micromol/l for men, 12.88+/-0.71 micromol/l for women). There were no significant associations between the levels and the presence or severity of CAD. The mutant MTHFR homozygotes tended to have higher levels and those with the MS and CBS mutations tended to have lower levels. We conclude that there is a significant correlation between plasma homocysteine levels and EC-SOD suggesting that elevated homocysteine may exert oxidative stress and that levels are associated with unstable angina, but not the occurrence or extent of coronary stenosis. The contributions to total plasma homocysteine levels of the common mutations of genes coding for the enzymes controlling homocysteine metabolism are modest.
Atherosclerosis 1999 Sep
PMID:Relationship between total plasma homocysteine, polymorphisms of homocysteine metabolism related enzymes, risk factors and coronary artery disease in the Australian hospital-based population. 1048 96

Oxygen free radicals as well as immunological reactions have been suggested to play important roles in atherogenesis and other pathological processes of the blood vessel wall. We have previously shown that the vascular wall contains exceptionally large amounts of extracellular superoxide dismutase (EC-SOD) and that the enzyme is produced and secreted to the extracellular space by the smooth muscle cells. In this work, we studied the influence of inflammatory cytokines on vascular smooth muscle cell expression of EC-SOD, the mitochondrial manganese superoxide dismutase (Mn-SOD) and the cytosolic copper zinc superoxide dismutase (CuZn-SOD). The expression of EC-SOD was up-regulated by interferon-gamma (IFN-gamma) and interleukin 4 (IL-4). and was down-regulated by tumor necrosis factor-alpha (TNF-alpha). The ratio between the maximal stimulation and depression observed was around 20-fold. The responses were slow and developed over periods of several days. The Mn-SOD activity was strongly up-regulated by TNF-alpha and IL-1alpha and moderately by IFN-gamma. The CuZn-SOD activity of the smooth muscle cells was not significantly influenced by any of the cytokines. The findings suggest that large changes in the SOD isoenzymes might occur in vascular diseases, significantly altering the susceptibility of the vascular wall to adverse effects of the superoxide radical.
Atherosclerosis 2000 Aug
PMID:Multiple cytokines regulate the expression of extracellular superoxide dismutase in human vascular smooth muscle cells. 1092 20

Reactive oxygen species have been proposed to play important roles in atherosclerosis. To investigate the protective role of extracellular superoxide dismutase (EC-SOD), its inhibition of endothelial-cell-mediated LDL oxidation was examined. We constructed the recombinant adenovirus AxCAEC-SOD expressing human EC-SOD by CAG promoter. Infection of endothelial cells with AxCAEC-SOD resulted in EC-SOD protein secretion in a dose-dependent manner and a decrease of endothelial-cell-derived superoxide production. Moreover, it was proven to coexist with heparan sulfate by immunohistochemical staining. Endothelial-cell-mediated LDL oxidation enhanced by ferric-sodium EDTA was inhibited by 47% in TBARS formation by AxCAEC-SOD infection. In agarose gel electrophoresis, AxCAEC-SOD decreased the negative charge of oxidized LDL by 50% and suppressed fragmentation of apolipoprotein B. These results suggested that human EC-SOD localized in the extracellular space and reduced endothelial-cell-mediated LDL oxidation. In subendothelial space, EC-SOD bound on heparan sulfate might suppress LDL oxidation through reduction of superoxide anion.
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PMID:Overexpression of EC-SOD suppresses endothelial-cell-mediated LDL oxidation. 1143 76

The common risk factors for atherosclerosis increase production of reactive oxygen species (ROS) by endothelial, vascular smooth muscle, and adventitial cells. These ROS initiate processes involved in atherogenesis through several important enzyme systems, including xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, and nitric oxide synthase. Physical forces also regulate vascular production of ROS. Oscillatory shear, which is present at sites where atherosclerosis develops, seems a particularly potent stimulus of superoxide production. The signaling cascade for activation of the NAD(P)H oxidase by angiotensin II has recently been elucidated and seems to involve a feed-forward mechanism that permits ongoing production of ROS for prolonged periods. Oxidative stress in humans with coronary artery disease is also exacerbated by a reduction of vascular extracellular superoxide dismutase, normally an important protective enzyme against the superoxide anion.
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PMID:Role of oxidative stress in atherosclerosis. 1264 38

Oxidative stress plays a pivotal role in the pathogenesis of atherosclerosis and can be effectively influenced by radical scavenging enzyme activity and expression. The vasoprotective effects of estrogens may be related to antioxidative properties. Therefore, effects of 17beta-estradiol on production of reactive oxygen species and radical scavenging enzymes were investigated. 17beta-estradiol diminished angiotensin II-induced free radical production in vascular smooth muscle cells (DCF fluorescence laser microscopy). 17beta-estradiol time- and concentration-dependently upregulated manganese (MnSOD) and extracellular superoxide dismutase (ecSOD) expression (Northern and Western blotting) and enzyme activity (photometric assay). Nuclear run-on assays demonstrated that 17beta-estradiol increases MnSOD and ecSOD transcription rate. Half-life of MnSOD mRNA was not influenced, whereas ecSOD mRNA was stabilized by estrogen. Copper-zinc SOD, glutathione-peroxidase, and catalase were not affected by estrogen. Estrogen deficiency in ovariectomized mice induced a downregulation of ecSOD and MnSOD expression, which was associated with increased production of vascular free radicals and prevented by estrogen replacement or treatment with PEG-SOD. In humans, increased estrogen levels led to enhanced ecSOD and MnSOD expression in circulating monocytes. Estrogen acts antioxidative at least to some extent via stimulation of MnSOD and ecSOD expression and activity, which may contribute to its vasoprotective effects.
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PMID:Modulation of antioxidant enzyme expression and function by estrogen. 1281 84

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O2-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or beta-galactosidase (beta-gal) reporter gene (5x10(10) plaque formation units [pfu]/mL), and the effect of transgene expression on O2- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ETA receptor antagonist ABT-627 (3x10(-8) mol/L), NADPH oxidase inhibitor apocynin (10(-4) mol/L), or dominant negative Rac1 gene transfer. The levels of O2- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not beta-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O2- from an ETA receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
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PMID:Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. 1451 26

Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine's deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteine-dependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteine-induced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.
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PMID:Influence of hyperhomocysteinemia on the cellular redox state--impact on homocysteine-induced endothelial dysfunction. 1465 25

The extracellular superoxide dismutase (ecSOD) plays an important role in atherosclerosis and endothelial function by modulating levels of the superoxide anion (O2*-) in the extracellular space. Although heparan sulfate proteoglycan is an important ligand for ecSOD, little is known about other biological binding partners of ecSOD. The goal of this study was to identify novel proteins that interact with ecSOD. A yeast two-hybrid screening of a human aorta cDNA library using ecSOD as bait identified fibulin-5 as a predominant binding protein for ecSOD. Further analysis showed that the binding domain of ecSOD within fibulin-5 mapped to its C-terminal domain. In vitro pulldown assays and coimmunoprecipitation analysis further confirmed that ecSOD interacts with fibulin-5 in vitro and in vivo. Studies using fibulin-5-/- mice indicated that fibulin-5 is required for binding of ecSOD to vascular tissue. Importantly, the decrease in tissue-bound ecSOD levels in aortas from fibulin-5-/- mice was associated with an increase in vascular O2*- levels. Furthermore, immunohistochemical analysis using ApoE-/- mice suggested a codistribution of ecSOD and fibulin-5 in atherosclerotic vessels. In summary, we provide in this study the first evidence that the ecSOD-fibulin-5 interaction is required for ecSOD binding to vascular tissues, thereby regulating vascular O2*- levels. This interaction may represent a novel mechanism for controlling vascular redox state in the extracellular space in various cardiovascular diseases such as atherosclerosis and hypertension in which oxidative stress is increased.
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PMID:Fibulin-5 is a novel binding protein for extracellular superoxide dismutase. 1552 65

The mechanisms of neointimal formation in cuff-injury models are still uncertain. To examine whether extracellular superoxide dismutase (EC-SOD) can reduce neointimal formation in a cuff-injury model, adenoviruses expressing EC-SOD (AxCAEC-SOD) or Escherichia coli beta-galactosidase (AxCALacZ) was injected between the cuff and the adventitia of rat femoral arteries. As a result, EC-SOD protein was effectively produced in the adventitia, as assessed by immunohistochemical staining. In comparison with cuff-treated control arteries and AxCALacZ-transfected arteries, neointimal formation was significantly reduced in AxCAEC-SOD-transfected arteries. Furthermore, proliferating smooth muscle cells in neointima and media were reduced by EC-SOD treatment. Similarly, augmented iNOS expression, apoptosis and collagen content in the vascular wall were also reduced by EC-SOD treatment. Reactive oxygen species (ROS) generation in tissue was reduced by EC-SOD expression, as assessed by dihydroethidium staining and coelenterazine chemiluminescence. These results suggest that ROS, especially superoxide anions at an adventitia, are responsible for neointimal formation in a cuff-injury model.
Atherosclerosis 2005 Jul
PMID:Extracellular superoxide dismutase overexpression reduces cuff-induced arterial neointimal formation. 1593 54


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