Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Altered trace elements and ascorbic acid metabolism have been implicated in the pathogenesis of atherosclerotic cardiovascular disease. However, their role in the disease process, or the effect of atherosclerosis on their tissue levels within plaque, is poorly understood. The present study analyzes the concentrations of Fe, Cu, Zn, and Mn, and ascorbic acid and superoxide dismutase (SOD) activity in tissue samples from 29 patients with abdominal aortic aneurysms (AAA) and 14 patients with atherosclerotic occlusive disease (AOD). It was observed that the Fe and Mn concentrations in AAA and AOD tissue were higher than the levels in nondiseased control aorta, whereas Cu and Zn levels in AAA and AOD tissue were similar to the levels in controls. The Zn:Cu ratio was significantly lower in the AAA tissue in comparison to both AOD and control tissue. In addition, AAA and AOD tissue had low ascorbic acid levels and low Cu,Zn-SOD activity with Cu,Zn-SOD:Mn-SOD ratios of 0.27 and 0.19, respectively, compared to a ratio of 3.20 in control aorta. These data indicate that aorta affected by aneurysms and occlusive disease have altered trace element and ascorbic acid concentrations, as well as low Cu,Zn-SOD activity. Although these observations do not directly support the hypothesis that AAA is associated with aortic Cu deficiency they do suggest a role for oxygen radicals or increased lipid peroxidation in occlusive and aneurysmal disease of the aorta.
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PMID:Aortic ascorbic acid, trace elements, and superoxide dismutase activity in human aneurysmal and occlusive disease. 380 68

Atherosclerotic lesions are found opposite vascular flow dividers at sites of low shear stress and oscillatory flow. Since endothelial proinflammatory genes prominent in lesions are regulated by oxidation-sensitive transcriptional control mechanisms, we examined the redox state of cultured human umbilical vein endothelial cells after either oscillatory or steady laminar fluid shear stress. Endothelial oxidative stress was assessed by measuring activity of the superoxide (O2.- )-producing NADH oxidase (a major source of reactive oxygen species in vascular cells), intracellular O2.- levels, induction of the redox-sensitive gene heme oxygenase-1 (HO-1), and abundance of Cu/Zn superoxide dismutase (Cu/Zn SOD), an antioxidant defense enzyme whose level of expression adapts to changes in oxidative stress. When cells were exposed to oscillatory shear (+/-5 dyne/cm2, 1 Hz) for 1, 5, and 24 hours, NADH oxidase activity and the amount of HO-1 progressively increased up to 174+/-16% (P<0.05) and 505+/-111% (P<0.05) versus static conditions, respectively, whereas levels of Cu/Zn SOD remained unchanged. This upregulation of HO-1 was completely blocked by the antioxidant N-acetylcysteine (NAC, 20 mmol/L). In contrast, steady laminar shear (5 dyne/cm2) induced NADH oxidase activity and NAC-sensitive HO-1 mRNA expression only at 1 and 5 hours, a transient response that returned toward baseline at 24 hours. Levels of Cu/Zn SOD mRNA and protein were increased after 24 hours of steady laminar shear. Furthermore, intracellular O2.-, as measured by dihydroethidium fluorescence, was higher in cells exposed to oscillatory than to laminar shear. These data are consistent with the hypothesis that continuous oscillatory shear causes a sustained activation of pro-oxidant processes resulting in redox-sensitive gene expression in human endothelial cells. Steady laminar shear stress initially activates these processes but appears to induce compensatory antioxidant defenses. We speculate that differences in endothelial redox state, orchestrated by different regimens of shear stress, may contribute to the focal nature of atherosclerosis.
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PMID:Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. 962 62

Oxidation of LDL in the subendothelial space has been proposed to play a key role in atherosclerosis. Endothelial cells produce superoxide anions (O2.-) and oxidize LDL in vitro; however, the role of O2.- in endothelial cell-induced LDL oxidation is unclear. Incubation of human LDL (200 microg/mL) with bovine aortic endothelial cells (BAECs) for 18 hours resulted in a 4-fold increase in LDL oxidation compared with cell-free incubation (22.5+/-1.1 versus 6.3+/-0.2 [mean+/-SEM] nmol malondialdehyde/mg LDL protein, respectively; P<0.05). Under similar conditions, incubation of LDL with porcine aortic endothelial cells resulted in a 5-fold increase in LDL oxidation. Inclusion of exogenous copper/zinc superoxide dismutase (Cu/ZnSOD, 100 microg/mL) in the medium reduced BAEC-induced LDL oxidation by 79%. To determine whether the intracellular SOD content can have a similar protective effect, BAECs were infected with adenoviral vectors containing cDNA for human Cu/ZnSOD (AdCu/ZnSOD) or manganese SOD (AdMnSOD). Adenoviral infection increased the content and activity of either Cu/ZnSOD or MnSOD in the cells and reduced cellular O2.- release by two thirds. When cells infected with AdCu/ZnSOD or AdMnSOD were incubated with LDL, formation of malondialdehyde was decreased by 77% and 32%, respectively. Two other indices of LDL oxidation, formation of conjugated dienes and increased LDL electrophoretic mobility, were similarly reduced by SOD transduction. These data suggest that production of O2.- contributes to endothelial cell-induced oxidation of LDL in vitro. Furthermore, adenovirus-mediated transfer of cDNA for human SOD, particularly Cu/ZnSOD, effectively reduces oxidation of LDL by endothelial cells.
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PMID:Overexpression of human superoxide dismutase inhibits oxidation of low-density lipoprotein by endothelial cells. 964 25

Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of cardiovascular diseases such as atherosclerosis. The localization of atherosclerotic lesions to arterial geometries associated with disturbed flow patterns suggests an important role for local hemodynamic forces in atherogenesis. There is increasing evidence that the vascular endothelium, which is directly exposed to various fluid mechanical forces generated by pulsatile blood flow, can discriminate among these stimuli and transduce them into genetic regulatory events. At the level of individual genes, this regulation is accomplished via the binding of certain transcription factors, such as NF kappa B and Egr-1, to shear-stress response elements (SSREs) that are present in the promoters of biomechanically inducible genes. At the level of multiple genes, distinct patterns of up- and downregulation appear to be elicited by exposure to steady laminar shear stresses versus comparable levels of non-laminar (e.g., turbulent) shear stresses or cytokine stimulation (e.g., IL-1 beta). Certain genes upregulated by steady laminar shear stress stimulation (such as eNOS, COX-2, and Mn-SOD) support vasoprotective (i.e., anti-inflammatory, anti-thrombotic, anti-oxidant) functions in the endothelium. We hypothesize that the selective and sustained expression of these and related "atheroprotective genes" in the endothelial lining of lesion-protected areas represents a mechanism whereby hemodynamic forces can influence lesion formation and progression.
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PMID:Endothelial dysfunction, hemodynamic forces, and atherogenesis. 1086 43

Endothelium-dependent relaxations mediated by NO are impaired in a mouse model of human atherosclerosis. Our objective was to characterize the mechanisms underlying endothelial dysfunction in aortas of apolipoprotein E (apoE)-deficient mice, treated for 26 to 29 weeks with a lipid-rich Western-type diet. Aortic rings from apoE-deficient mice showed impaired endothelium-dependent relaxations to acetylcholine (10(-)(9) to 10(-)(5) mol/L) and Ca(2+) ionophore (10(-)(9) to 10(-)(6) mol/L) and endothelium-independent relaxations to diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate, 10(-)(10) to 10(-)(5) mol/L) compared with aortic rings from C57BL/6J mice (P<0.05). By use of confocal microscopy of an oxidative fluorescent probe (dihydroethidium), increased superoxide anion (O(2)(-)) production was demonstrated throughout the aortic wall but mainly in smooth muscle cells of apoE-deficient mice. CuZn-superoxide dismutase (SOD) and Mn-SOD protein expressions were unaltered in the aorta exposed to hypercholesterolemia. A cell-permeable SOD mimetic, Mn(III) tetra(4-benzoic acid) porphyrin chloride (10(-)(5) mol/L), reduced O(2)(-) production and partially normalized relaxations to acetylcholine and DEA-NONOate in apoE-deficient mice (P<0.05). [(14)C]L-Citrulline assay showed a decrease of Ca(2+)-dependent NOS activity in aortas from apoE-deficient mice compared with C57BL/6J mice (P<0.05), whereas NO synthase protein expression was unchanged. In addition, cGMP levels were significantly reduced in the aortas of apoE-deficient mice (P<0.05). Our results demonstrate that in apoE-deficient mice on a Western-type fat diet, impairment of endothelial function is caused by increased production of O(2)(-) and reduced endothelial NO synthase enzyme activity. Thus, chemical inactivation of NO with O(2)(-) and reduced biosynthesis of NO are key mechanisms responsible for endothelial dysfunction in aortas of atherosclerotic apoE-deficient mice.
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PMID:Mechanism of endothelial dysfunction in apolipoprotein E-deficient mice. 1139 13

Gene transfer may be appropriate for therapeutic protocols targeted at the vascular endothelium. Endothelial dysfunction is the principal phenotype associated with atherosclerosis and hypertension. Oxidative stress has been implicated in the development of endothelial dysfunction. We have explored the ability of overexpressing anti-oxidant genes (superoxide dismutases; SODs) in vitro and in vivo to assess their potential for reversing endothelial dysfunction in a rat model, the stroke-prone spontaneously hypertensive rat (SHRSP). Western blotting and immunofluorescence assays in vitro showed efficient overexpression of MnSOD and ECSOD with respect to localisation to the mitochondria and extracellular surface, respectively. Transgene functional activity was quantified with SOD activity assays. MnSOD and ECSOD overexpression in intact SHRSP vessels in vivo led to endothelial and adventitial overexpression. Pharmacological assessment of transduced vessels following in vivo delivery by basal NO availability quantification demonstrated that the "null" adenovirus and MnSOD adenovirus did not significantly increase NO availability. However, AdECSOD-treated carotid arteries showed a significant increase in NO availability (1.91 +/- 0.04 versus 0.75 +/- 0.08 g/g, n = 6, P = 0.029). In summary, efficient overexpression of ECSOD, but not MnSOD in vivo, results in improved endothelial function in a rat model of hypertension and has important implications for the development of endothelial-based vascular gene therapy.
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PMID:Adenovirus-mediated overexpression of extracellular superoxide dismutase improves endothelial dysfunction in a rat model of hypertension. 1185 69

Extracellular-superoxide dismutase (EC-SOD) [EC 1.15.1.1] is a secretory glycoprotein with an affinity for heparin-like proteoglycans. This enzyme locates in blood vessel walls at high levels and may be important for the antioxidant capability of vascular walls. Oxidative process plays an important role in atherogenesis. Lysophosphatidylcholine (lysoPC) is generated during oxidation of low-density lipoprotein (LDL) and is located within atherosclerotic plaques. Recently, lysoPC has been reported to induce transcription of a variety of cellular genes. In this study, we observed that lysoPC significantly increased the expression of EC-SOD mRNA and protein in human monocytic U937 cells, but not those of CuZn-SOD or Mn-SOD. Induced EC-SOD by lysoPC had a high affinity for heparin, and may bind to the endothelial cell surface. Very recently, it has been reported that exogenous addition of EC-SOD or overexpression of EC-SOD prevented endothelial cell-mediated oxidative modification of LDL. Therefore, it is speculated that EC-SOD is induced by lysoPC-stimulated monocytes as a feedback mechanism in vascular homeostasis.
Atherosclerosis 2002 Aug
PMID:The expression of extracellular-superoxide dismutase is increased by lysophosphatidylcholine in human monocytic U937 cells. 1205 68

Platelets have been implicated in the pathogenesis of different diseases of the vascular system, including atherosclerosis, sepsis, and ischemia-reperfusion injury; however, relatively little is known about the factors that regulate the interactions between circulating platelets and the vessel wall. The objective of this study was to define the contribution of superoxide to LPS-induced platelet-endothelial cell (P/E) adhesion in murine intestinal venules. The adhesion of rhodamine-6G-labeled murine platelets was monitored by intravital fluorescence microscopy. Four hours after LPS administration in control [wild-type (WT)] mice, an approximately 10-fold increase in P/E adhesion was detected. This response did not result from LPS-induced platelet activation. The LPS-induced P/E adhesion was greatly attenuated in NAD(P)H oxidase-deficient mice and in WT mice rendered neutropenic with anti-neutrophil serum, whereas the response was unchanged in WT mice receiving a CD18 blocking MAb or in CD18-deficient mice. A chimeric form of MnSOD that exhibits the binding properties of extracellular SOD also attenuated the LPS-induced response in WT mice. These findings indicate that neutrophil-derived superoxide plays a major role in the modulation of endotoxin-induced P/E adhesion.
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PMID:Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. 1238 24

The markers of the bioavailability of NO (endothelium-dependent relaxation to acetylcholine and cyclic GMP content) in the thoracic aorta of apolipoprotein-E-deficient (ApoE KO) mice, 20 weeks old with enriched cholesterol diet or 35 weeks old on regular chow, are not decreased, in contrast with other models of atherosclerosis. However, severe hypercholesterolemia, the presence of atherosclerotic lesions and increased NADPH oxidase activity have been reported as early as at 20 weeks of age. The present experiments were designed to test if an increased capacity of NO production in these mice explains this paradox. The expressions of the 3 isoforms of NO synthase (NOS) were compared in ApoE KO and C57Bl/6J mice using Western blot and localized by immunohistochemistry. No adaptive increase in the expression of NOS was detected in ApoE KO mice. NO bioavailability could also be preserved by upregulation of enzymes involved in redox status such as CuZn or Mn superoxide dismutase and catalase. However, these enzymes were less expressed in ApoE KO mice than in control mice. These results highlight that ApoE KO mice represent an atypical model of atherosclerosis.
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PMID:Persistence of the nitric oxide pathway in the aorta of hypercholesterolemic apolipoprotein-E-deficient mice. 1280 44

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


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