UMLS:C0004153 - FACTA Search

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

The aim of the study as to assess the influence of the physiological aging process on the platelet cell metabolism in middle-aged people. A group of 17 healthy women (aged 47-59 years), and a group of healthy men (aged 45-60 years) were examined. The control group was composed of healthy women aged 19-25 years, and healthy men aged 19-27 years. The activity of hyperoxide dismutase, catalase, glutathione peroxidase and the concentration of malonyldialdehyde were determined in platelets. In comparison to the control group, a significant decrease in the activity of hyperoxide dismutase and glutathione peroxidase as well as an enhanced concentration of malonyldialdehyde were observed in the group studied. Moreover, a diminished catalase activity was noted in platelets of men, while in women there were no significant changes. The study indicated that disorders in the function of thrombocytes, an excessive generation of oxygen free radicals, and impaired mechanisms of cellular antioxidative defence accelerate atherosclerosis and aging process. Therefore, it is necessary to cover middle-aged people, particularly those occupationally exposed to factors affecting defence mechanisms, with adequate preventive programmes.
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PMID:[Platelets oxygen metabolism in women and men in different age groups]. 981 79

Acute hyperglycemia may contribute to the progression of atherosclerosis by regulating protein kinase C (PKC) isozymes and by accelerating vascular smooth muscle cell (VSMC) proliferation. We investigated acute glucose regulation of PKCbeta gene expression in A10 cells, a rat aortic smooth muscle cell line. Western blot analysis showed that PKCbetaII protein levels decreased with high glucose (25 mM) compared to normal glucose (5.5 mM), whereas PKCbetaI levels were unaltered. PKCbeta mRNA levels were depleted by 60-75% in hyperglycemic conditions. To elucidate whether high glucose regulated PKCbeta expression via the common promoter for PKCbetaI and PKCbetaII, deletion constructs of the PKCbeta promoter ligated to CAT as reporter gene were transfected into A10 cells. Construct D (-411 to +179CAT) showed quenching in high glucose (25 mM) and suggested the involvement of a carbohydrate response element in the 5' promoter region of the PKCbeta gene. In actinomycin D-treated A10 cells, a 60% decrease in PKCbeta mRNA with high glucose treatment indicated that posttranscriptional destabilization by glucose was also occurring. We have demonstrated that glucose-induced posttranscriptional destabilization of PKCbetaII message is mediated via a nuclease activity present in the cytosol. The specificity of glucose to posttranscriptionally destabilize PKCbetaII mRNA, but not the PKCbetaI mRNA, was confirmed in both A10 cells and primary cultures from human aorta.
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PMID:Acute hyperglycemia regulates transcription and posttranscriptional stability of PKCbetaII mRNA in vascular smooth muscle cells. 987 35

1. Elevated plasma levels of homocysteine (HC) and copper have both been associated with the development of inflammatory vascular diseases, such as atherosclerosis. In this study, the effects of a combination of HC and copper on nitric oxide (NO)-mediated relaxation of isolated rat aortic rings were investigated. 2. Exposure to HC (10-100 microM; 30 min) had no effect on relaxation to acetylcholine (ACh; 0.01-10 microM, n=4). Pre-incubation of aortic rings with a higher concentration of HC for an extended period (1 mM; 180 min) significantly inhibited endothelium-dependent relaxation (n=4), but this inhibition was prevented by the presence of the copper chelator bathocuprione (10 microM, 180 min, n=6). 3. Exposure to HC (100 microM) and copper (10-100 microM; 30 min) caused a copper concentration-dependent inhibition of endothelium-dependent relaxation (n=4). This inhibitory effect was reduced in the presence of either superoxide dismutase (SOD; 100 u ml(-1); n=4) or catalase (100 u ml(-1); n=4), and further reduced by the presence of both enzymes (n=5). 4. HC and copper (100 microM; 30 min) significantly inhibited endothelium-independent relaxation to glyceryl trinitrate (0.01-10 microM; n=8). In contrast, HC (1 mM), alone or in combination with copper (100 microM), did not inhibit relaxation to the endothelium-independent relaxant sodium nitroprusside (0.01-10 microM; n=4). 5. These data indicate that the presence of copper greatly enhances the inhibitory actions of HC on NO-mediated relaxation of isolated aortic rings. The reduction of inhibition by catalase and SOD indicates a possible role for copper-catalyzed generation of superoxide and hydrogen peroxide leading to an increased inactivation or decreased production of endothelium-derived NO.
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PMID:Investigation of the inhibitory effects of homocysteine and copper on nitric oxide-mediated relaxation of rat isolated aorta. 1019 85

Cardiovascular disease is the leading cause of morbidity and mortality in westernized populations. Low levels of alpha-tocopherol (AT) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective. Recently, we showed that supplementation with AT resulted in significant decreases in monocyte superoxide anion release, lipid oxidation, interleukin-1 beta (IL-1 beta) release, and adhesion to endothelium. The reduction in superoxide and lipid oxidation by AT seemed to be mediated by inhibition of protein kinase C. The aim of this study was to investigate the mechanism(s) by which AT inhibits IL-1 beta release. Potential mechanisms examined included its effect as an antioxidant and its inhibitory effects on protein kinase C and the cyclooxygenase-lipoxygenase pathways. Although AT decreased superoxide release from activated monocytes, superoxide dismutase and catalase had no effect on IL-1 beta release. Also, a similar antioxidant, beta-tocopherol, had no effect on IL-1 beta release. The protein kinase C inhibitor, bisindolylmaleimide, did not inhibit IL-1 beta release from activated monocytes, in spite of AT decreasing protein kinase C activity. Leukotriene B4, a major product of 5-lipoxygenase, has been shown to augment IL-1beta release. In the presence of AT, a significant reduction in leukotriene B4 and IL-1 beta levels was observed, which was reversed by the addition of leukotriene B4. Similar observations were seen with specific inhibitors of 5-lipoxygenase. The product of cyclooxygenase, prostaglandin E2, has been shown to inhibit IL-1 beta activity in some systems. However, AT had no significant effect on prostaglandin E2 levels in activated monocytes. In the presence of indomethacin, a cyclooxygenase inhibitor, AT inhibited IL-1 beta activity. Also, AT had no effect on IL-1 beta mRNA levels or stability, suggesting a posttranscriptional effect. Thus, in activated human monocytes, AT exerts a novel biological effect of inhibiting the release of the proinflammatory cytokine, IL-1 beta, via inhibition of the 5-lipoxygenase pathway.
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PMID:Alpha-tocopherol decreases interleukin-1 beta release from activated human monocytes by inhibition of 5-lipoxygenase. 1019 45

Low density lipoprotein (LDL) oxidation is a major contributor to foam cell formation during early atherogenesis. Several oxygenases have been implicated in the process of LDL oxidation in the arterial wall, where the environment is relatively low in antioxidants, but the exact mechanism for LDL oxidation in vivo is not known. In the present study we sought to determine the ability of cytochrome P450 2E1 (P450 2E1) and other P450s, located in the liver and in other tissues, to oxidize LDL. Upon incubation of LDL (0.1 mg of protein/ml) with purified, reconstituted rabbit P450 2E1 in the presence of NADPH and the NADPH-cytochrome P450 reductase, time- and P450 2E1 concentration-dependent LDL oxidation was observed, as analyzed by determining the formation of peroxides, thiobarbituric acid reactive substances (TBARS), and conjugated dienes. Within 1 h of initiating the reaction, almost maximal oxidation was observed. NADPH, and active P450 2E1 enzyme were required for LDL oxidation to occur. The rate of P450 2E1-induced LDL oxidation was also dependent on the lipoprotein concentration. P450 2E1 could also oxidize pure phospholipids and cholesteryl ester, the major lipids in LDL. In the presence of catalase or superoxide dismutase (SOD), LDL oxidation was completely blocked, suggesting that hydrogen peroxide and superoxide are involved in P450 2E1-induced LDL oxidation. The ability of P450 2E1 to oxidize LDL was not unique to this enzyme, and could be observed with some other purified, cytochromes P450 in the reconstituted system such as rat P450 2B1 and human P450 3A4. Finally, microsomal membranes obtained from rats that were induced to express high levels of P450s 2B1, 2E1, and 1A1/2 were able to oxidize LDL, whereas little oxidation was seen with microsomes that were induced to express 3A2. We thus conclude that LDL can be oxidized by some cytochrome P450s and, as some of these enzymes are present in liver and in arterial wall, they may have a physio/pathological relevance to LDL oxidation and atherogenesis.
Atherosclerosis 1999 Apr
PMID:Microsomal cytochromes P450 catalyze the oxidation of low density lipoprotein. 1021 53

Various lines of evidence indicate that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of atherosclerosis and coronary heart disease. We have investigated the effect of modified (oxidized) low-density lipoproteins (oxLDL) on collagen and fibronectin synthesis in cultured human coronary artery smooth muscle cells (HCA-SMC). As shown by immunofluorescence microscopy and time-resolved fluorescence immunoassay, oxLDL dose-dependently stimulated collagen type I and fibronectin synthesis in cultured HCA-SMC. The effect on matrix synthesis was biphasic, with a maximum effect at concentrations between 1 and 10 microg/ml oxLDL. Higher oxLDL concentrations (>25 microg/ml) were cytotoxic. Beside oxLDL, malondialdehyde-modified LDL also stimulated extracellular matrix synthesis. In the presence of 100 microg/ml ascorbic acid, 25, 50 and 100 microg/ml oxLDL induced apoptosis within 6-8 hours (demonstrated by TUNEL-reaction, annexin-V binding and APO-2.7-expression). Apoptosis was not induced by normal (unmodified) LDL and malondialdehyde-modified LDL. The radical scavengers and antioxidants TROLOX and probucol and the hydrogen peroxide eliminator catalase significantly reduced oxLDL-induced apoptosis. Our results demonstrate that low concentrations of oxLDL are profibrogenic by stimulating extracellular matrix synthesis, whereas higher oxLDL concentrations induce oxidative stress and apoptosis in coronary artery smooth muscle cells. The profibrogenic effect might be relevant in the formation of atherosclerotic plaques, and the proapoptotic effect might contribute to an increased plaque vulnerability.
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PMID:Depending on their concentration oxidized low density lipoproteins stimulate extracellular matrix synthesis or induce apoptosis in human coronary artery smooth muscle cells. 1035 78

Oxidized LDL is implicated in atherosclerosis; however, the pathways that convert LDL into an atherogenic form in vivo are not established. Production of reactive nitrogen species may be one important pathway, since LDL recovered from human atherosclerotic aorta is enriched in nitrotyrosine. We now report that reactive nitrogen species generated by the MPO-H2O2-NO2- system of monocytes convert LDL into a form (NO2-LDL) that is avidly taken up and degraded by macrophages, leading to massive cholesterol deposition and foam cell formation, essential steps in lesion development. Incubation of LDL with isolated MPO, an H2O2-generating system, and nitrite (NO2-)-- a major end-product of NO metabolism--resulted in nitration of apolipoprotein B 100 tyrosyl residues and initiation of LDL lipid peroxidation. The time course of LDL protein nitration and lipid peroxidation paralleled the acquisition of high-affinity, concentration-dependent, and saturable binding of NO2-LDL to human monocyte-derived macrophages and mouse peritoneal macrophages. LDL modification and conversion into a high-uptake form occurred in the absence of free metal ions, required NO2-, occurred at physiological levels of Cl-, and was inhibited by heme poisons, catalase, and BHT. Macrophage binding of NO2-LDL was specific and mediated by neither the LDL receptor nor the scavenger receptor class A type I. Exposure of macrophages to NO2-LDL promoted cholesteryl ester synthesis, intracellular cholesterol and cholesteryl ester accumulation, and foam cell formation. Collectively, these results identify MPO-generated reactive nitrogen species as a physiologically plausible pathway for converting LDL into an atherogenic form.
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PMID:Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. 1035 64

The effect of oxidative modification of high-density lipoprotein (HDL) was assessed by incubation of normal HDL (obtained from Rhesus monkeys fed a stock diet) with 5 microM CuSO4 at 37 degrees C for 12 h/24 h. The physicochemical properties of oxidized-HDL (Ox-HDL) were found to be affected in terms of lipid peroxidation, as observed by the increased level of thiobarbituric acid reactive substances (nmol MDA/mg HDL protein). The biological properties of HDL were altered, since a decrease in the efflux of free cholesterol into the medium was found in the presence of Ox-HDL24h compared with normal HDL (N-HDL). The binding, uptake and degradation of 125I-LDL by macrophages increased in the presence of Ox-HDL24h. The activity of antioxidant enzymes (superoxide dismutase, catalase and glutathione-peroxidase) was reduced in monocytes in the presence of Ox-HDL. However, in the presence of N-HDL, the levels of antioxidant enzymes were maintained at a higher level than in the control (in the absence of HDL) monocytes. Furthermore, the number of monocytes adhered to aortic endothelium were found to be increased in the presence of Ox-HDL. These findings suggest that HDL is susceptible to oxidative modification. Since the parameters selected in the present study are involved in the pathogenesis of atherosclerosis, it can be postulated that the in vivo protection of HDL in atherosclerosis can be reversed in the circumstances in which HDL undergoes oxidative modification like low-density lipoprotein (LDL).
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PMID:The role of oxidized HDL in monocyte/macrophage functions in the pathogenesis of atherosclerosis in Rhesus monkeys. 1040 Jan 66

In humans, increased plasma homocysteine (Hcy) has been shown to be correlated with occlusive arterial diseases and atherosclerosis. Studies of isolated conductance vessels of experimental animals suggest that Hcy may interfere with local vasoregulatory mechanisms, yet the effect of hyperhomocysteinemia (HHcy) on the function of microvessels, such as skeletal muscle arterioles, has not been investigated. Male Wistar rats were divided into 2 groups: control rats (C; plasma Hcy, 7.1+/-0.3 micromol/L; n=25), and rats made HHcy by 1 g/kg body weight daily intake of methionine in the drinking water for 4 weeks (plasma Hcy, 23.6+/-2.9 micromol/L; P<0.01 versus C; n=25). First-order arterioles ( approximately 130 micrometer in diameter) were isolated from gracilis muscle, cannulated, and pressurized (80 mm Hg, no-flow conditions). Changes in diameter were observed by videomicroscopy. Arteriolar constrictions to norepinephrine (NE; 3x10(-7) mol/L) were significantly (P<0.01) greater in HHcy compared with C rats (C, 37.7+/-4.9%; HHcy, 59.5+/-5. 2%). Removal of the endothelium (-E) augmented NE-induced constrictions only in arterioles from C rats, whereas it had no effect on responses of arterioles from HHcy rats (C-E, 55.9+/-6.9%; HHcy-E, 56.5+/-7.0%). Dilations to cumulative doses of acetylcholine (ACh; 10(-8) mol/L) were significantly reduced in arterioles from HHcy rats (C, 64.0+/-5.2%; HHcy, 24.1+/-6.8%). Inhibition of nitric oxide (NO) synthesis with N(omega)-nitro-L-arginine (L-NNA; 10(-4) mol/L) significantly decreased ACh-induced dilations of C arterioles, whereas it did not affect HHcy arterioles. Similar alterations were found in arteriolar dilations to histamine, another known NO-dependent agonist. Endothelium-independent dilations to the NO donor sodium nitroprusside were not different in arterioles from C and HHcy rats, either in the presence or absence of L-NNA. Presence of superoxide dismutase and catalase (scavenger of reactive oxygen metabolites) did not affect HHcy-induced alterations in the ACh response. We conclude that hyperhomocysteinemia reduces rat skeletal muscle arteriolar dilations in response to ACh and histamine, and enhances constrictions to NE, alterations that are likely to be caused by the reduced mediation of these responses by NO. The reduced activity of NO in arterioles may contribute to the microvascular impairment described in HHcy.
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PMID:Dysfunction of nitric oxide mediation in isolated rat arterioles with methionine diet-induced hyperhomocysteinemia. 1044 68

Reactive oxygen metabolites such as hydrogen peroxide (H(2)O(2)) and oxidized fatty acids are proinflammatory and are involved in the pathophysiology of various diseases including atherosclerosis. The effects of these oxidants could be inhibited by the external addition of an antioxidant, suggesting the promotion or propagation of further oxidation. In this study, we describe the stable overexpression of human catalase in smooth muscle cells and the resistance of these cells to cytotoxicity induced not only by the addition of H(2)O(2) but also by the addition of 13-hydroperoxyoctadecadienoic acid (13-HPODE). The results pose an intriguing possibility of the generation of H(2)O(2) from a peroxidized fatty acid. Accordingly, incubation of cells with both 13-HPODE and 13-hydroxyoctadecadienoic acid resulted in the generation of intracellular H(2)O(2). To explain the observed results by which catalase could overcome the effects of 13-HPODE, we propose that oxidized fatty acids are degraded in the cellular peroxisomes, resulting in the generation of H(2)O(2). In other words, the cellular effects of peroxidized fatty acids could be attributed to the generation of H(2)O(2).
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PMID:Overexpression of human catalase gene decreases oxidized lipid-induced cytotoxicity in vascular smooth muscle cells. 1044 70

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