Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Linoleic acid hydroperoxide (LoaOOH) formed during free radical attack on long-chain unsaturated fatty acids is an important source of biomembrane damage and is implicated in the onset of atherosclerosis, hepatic diseases, and food rancidity. LoaOOH is toxic to wild-type Saccharomyces cerevisiae at a very low concentration (0.2 mM) relative to other peroxides. By using isogenic mutant strains, the possible roles of glutathione (gsh1 and gsh2), glutathione reductase (glr1), respiratory competence ([rho0] petite), and yAP-1p-mediated expression (yap1) in conferring LoaOOH resistance have been examined. Respiration-related processes were essential for maximal toxicity and adaptation, as evidenced by the fact that the [rho0] petite mutant was most resistant to LoaOOH but could not adapt. Furthermore, when respiration was blocked by using inhibitors of respiration and mutants defective in respiratory-chain components, cells became more resistant. An important role for reduced glutathione and yAP-1 in the cellular response to LoaOOH was shown, since the yap1 and glr1 mutants were more sensitive than the wild type. In addition, total glutathione peroxidase activity increased following treatment with LoaOOH, indicating a possible detoxification role for this enzyme. Yeast also showed an adaptive response when pretreated with a nonlethal dose of LoaOOH (0.05 mM) and subsequently treated with a lethal dose (0.2 mM), and de novo protein synthesis was required, since adaptation was abolished upon treatment of cells with cycloheximide (25 microg ml-1). The wild-type adaptive response to LoaOOH was independent of those for the superoxide-generating agents paraquat and menadione and also of those for the organic hydroperoxides cumene hydroperoxide and tert-butyl hydroperoxide. Pretreatment with LoaOOH induced resistance to hydrogen peroxide, while pretreatment of cells with malondialdehyde (a lipid peroxidation product) and heat shock (37 degrees C) gave cross-adaptation to LoaOOH, indicating that yeast has effective overlapping defense systems that can detoxify fatty acid hydroperoxides directly or indirectly.
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PMID:Toxicity of linoleic acid hydroperoxide to Saccharomyces cerevisiae: involvement of a respiration-related process for maximal sensitivity and adaptive response. 945 48

To obtain further insight into the role of erythrocyte antioxidant systems in the development of atherosclerosis, intraerythrocyte enzyme activities and selenium levels in erythrocytes were determined in 37 patients with angiographically proved coronary artery stenosis and 15 subjects with normal coronary angiograms as controls. In a preliminary study, the enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR) and selenium-dependent glutathione peroxidase (Se-GPx) were measured in both venous and arterial blood samples obtained from patients before angiography. The data of the preliminary study, which showed that only the Se-GPx decreased in the patients, led us to concentrate on the Se-GPx and Se levels to determine the changes in these variables. Our results showed that there was a decrease in both the activity of Se-GPx and Se levels in erythrocytes parallel to the increase in the severity of coronary artery disease. It was concluded that these parameters might be used as determinants in the assessment of the severity of the disease.
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PMID:Erythrocyte selenium-glutathione peroxidase activity is lower in patients with coronary atherosclerosis. 948 32

The Japanese quail has been used as a model of human atherosclerosis to investigate the mechanisms underlying the development of vascular lesions, i.e. hyperlipoproteinaemia and impaired endogenous antioxidant status. In the present study, Japanese quail were fed on semi-purified diets containing butter, beef tallow or soyabean-oil blends, with either 0.5 or 5 g cholesterol/kg for 9 weeks to examine the effects of dietary fat blends varying in fatty acid composition and cholesterol intake on plasma lipids and aortic atherosclerotic plaque and sterol composition. These findings were related to possible diet-induced changes in antioxidant status of selected tissues. Hypercholesterolaemia was confirmed (P < 0.001) in birds fed on high-cholesterol (HC) diets. Plasma total cholesterol concentration and cholesterol content of lipoprotein fractions in hypercholesterolaemic birds were lower (P < 0.05) in quail fed on the soyabean-oil blend. Plasma triacylglycerol content was increased (P < 0.001) in HC-fed birds. Dietary fat blends did not influence plasma triacylglycerol levels. Tissue antioxidant status (catalase (EC 1.11.1.6), glutathione peroxidase (EC 1.11.1.9), glutathione reductase (EC 1.6.4.1) and superoxide dismutase (EC 1.15.1.1) activities and glutathione content) was generally not greatly affected by dietary fat blend or cholesterol treatment. Birds fed on HC diets exhibited severe (P < 0.001) atherosclerotic plaque in aortas which was not influenced by the source of dietary fat blend. Scanning electron microscopy confirmed results of visual aortic plaque scoring using dissecting light microscopy. Several cholesterol oxides were identified and quantified in aortic plaque from HC-fed birds (5,6 alpha-epoxy-5 alpha-cholesterol, 7(beta-hydroxycholesterol and 7-ketocholesterol) regardless of dietary fat blend. The results indicate that dietary fat blends varying in polyunsaturated:saturated fatty acid ratios only marginally influence the degree of hypercholesterolaemia in atherosclerosis-susceptible quail fed on atherogenic diets only, and are not a factor, compared with sterol feeding, in modulating the degree of atherosclerosis or the aortic oxysterol content in these same birds. Moreover, diet-induced hyperlipoproteinaemia had only a small effect on antioxidant status of selected tissues examined.
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PMID:Influence of dietary cholesterol and fat source on atherosclerosis in the Japanese quail (Coturnix japonica). 949 48

The objective of the present study was to investigate the expression of major xenobiotic-metabolising cytochrome P450 proteins, and of other enzyme systems, in hepatic and extrahepatic tissues of rabbits rendered atherosclerotic by the dietary administration of 1% cholesterol diets for 8 weeks. Individual cytochrome P450 proteins were monitored using diagnostic substrates and immunologically in Western blot analysis. The activity of all hepatic isoforms studied was depressed in the atherosclerotic animals; when, however, apoprotein levels were determined immunologically, no major differences were evident between the control and the atherosclerotic rabbits. In vitro studies indicated that neither cholesterol nor palm oil inhibited cytochrome P450 activity. The effects of cholesterol treatment leading to atherosclerosis on kidney, heart and lung cytochrome P450 activities were isoform- and tissue-specific; no change was evident in the heart activities, but in the lung and kidney cytochrome P450 activities were clearly modulated by the treatment with cholesterol. Apoprotein levels did not always parallel the changes in activities. Western blot analysis of aortic cytochromes P450 revealed that administration of cholesterol-rich diets enhanced CYP2B and CYP3A apoprotein levels. Cholesterol feeding to rabbits gave rise to a marked decrease in hepatic glutathione S-transferase activity but did not influence glutathione reductase or total glutathione levels. The same treatment had no effect on catalase, glutathione peroxidase and superoxide dismutase. It is concluded that treatment of rabbits with cholesterol-rich diets leading to atherosclerosis gives rise to profound changes in the expression of cytochrome P450 proteins in the liver and other tissues; possible mechanisms are discussed.
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PMID:Marked inhibition of hepatic cytochrome P450 activity in cholesterol-induced atherosclerosis in rabbits. 967 66

Atherosclerotic plaques contain a significant number of macrophage foam cells and are associated with an inflammatory state. Inflammation induces the secretion from monocytes and other cells of cytokines, reactive oxygen species, proteinases and proteinase inhibitors among many other molecular species. AAT is prominent among the serine proteinase inhibitors and is an important regulator of leukocyte elastase and proteinase-3. It has been shown that the stable AAT-proteinase complex can upregulate AAT biosynthesis, and we have shown that the shorter, carboxyl terminal peptide (C-36) resulting from proteinase cleavage of AAT polymerizes, and in its fibrillar form alters cellular metabolism. To test for a possible link between the inflammation-generated C-36 peptide and cellular processes associated with atherogenesis, we have studied the effects of the fibrillar form of this peptide at varying concentrations on human monocytes in culture. We have found that fibrillar C-36 at concentrations of greater than or equal to 5 micromol/l in monocyte cultures for 24 h significantly increases LDL binding and uptake, upregulates LDL receptors, induces cytokine production and glutathione reductase activity, and upregulates AAT synthesis. The expression of CD36 protein, LDL Scavenger receptor, is also upregulated by fibrillar C-36 and native LDL in the presence of C-36-activated monocytes is more oxidized than with unactivated control monocytes. The majority of monocytes cultured for 24 h in the presence of C-36 fibrils were transformed morphologically into macrophages. These data establish a direct molecular link, mediated by C-36 peptide of AAT, between inflammation and the oxidation and accumulation of lipid in monocyte-derived macrophages. This may be important for an understanding of the events conducive to atherogenesis.
Atherosclerosis 1999 Dec
PMID:Atherogenic properties of human monocytes induced by the carboxyl terminal proteolytic fragment of alpha-1-antitrypsin. 1055 12

Aldose reductase has been implicated in the etiology of diabetic complications, atherosclerosis, and ischemia-reperfusion injury. Aldose reductase inhibitors are known to have species-dependent differences in biotransformation enzyme induction. Whether aldose reductase inhibitors, which have antioxidant potential, alter the oxidative stress pathway is unknown. This study has determined whether four daily ip treatments of either low (10 mg/kg) or high (50 mg/kg) doses of AL-1576 or AL-4114 alter the activities of the antioxidant defense enzymes catalase, glutathione reductase, glutathione peroxidase, superoxide dismutase, and the concentrations of reduced and oxidized glutathione in livers of normal rats and rabbits. There was no change in the concentration of thiobarbituric acid reactive substances in either rat or rabbit livers, indicating that lipid peroxidation was not increased by any treatment. Hepatic catalase, superoxide dismutase, and glutathione peroxidase activities and concentrations of reduced and oxidized glutathione were not significantly altered in rat, though glutathione reductase activity was increased after high doses of both drugs. However, in rabbit liver, glutathione reductase activity decreased in a dose-dependent manner after AL-4114 treatment, while superoxide dismutase and glutathione peroxidase activities decreased only after the low dose of AL-4114. Although AL-4114 and AL-1576 did not directly generate increased lipid peroxidation within normal rat and rabbit livers, some of the enzymes responsible for oxidative defense were altered, particularly in rabbit livers.
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PMID:Effects of aldose reductase inhibitors on antioxidant defense in rat and rabbit liver. 1065 32

Although philosophers and scientists have long been interested in the aging process, general interest in this fascinating and highly important topic was minimal before the 1960s. In recent decades, however, interest in aging has greatly accelerated, not only since the elderly form an ever-increasing percentage of the population, but because they utilize a significant proportion of the national expenditures. In addition, many people have come to the realization that one can now lead a very happy, active, and productive life well beyond the usual retirement age. Scientifically, aging is an extremely complex, multifactorial process, and numerous aging theories have been proposed; the most important of these are probably the genomic and free radical theories. Although it is abundantly clear that our genes influence aging and longevity, exactly how this takes place on a chemical level is only partially understood. For example, what kinds of genes are these, and what proteins do they control? Certainly they include, among others, those that regulate the processes of somatic maintenance and repair, such as the stress-response systems. The accelerated aging syndromes (i.e., Hutchinson-Gilford, Werner's, and Down's syndromes) are genetically controlled, and studies of them have decidedly increased our understanding of aging. In addition, C. elegans and D. melanogaster are important systems for studying aging. This is especially true for the former, in which the age-1 mutant has been shown to greatly increase the life span over the wild-type strain. This genetic mutation results in increased activities of the antioxidative enzymes, Cu-Zn superoxide dismutase and catalase. Thus, the genomic and free radical theories are closely linked. In addition, trisomy 21 (Down's syndrome) is characterized by a significantly shortened life span; it is also plagued by increased oxidative stress which results in various free radical-related disturbances. Exactly how this extra chromosome results in an increased production of reactive oxygen species is, however, only partially understood. There is considerable additional indirect evidence supporting the free radical theory of aging. Not only are several major age-associated diseases clearly affected by increased oxidative stress (atherosclerosis, cancer, etc.), but the fact that there are numerous natural protective mechanisms to prevent oxyradical-induced cellular damage speaks loudly that this theory has a key role in aging [the presence of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, among others; various important intrinsic (uric acid, bilirubin, -SH proteins, glutathione, etc.) and extrinsic (vitamins C, E, carotenoids, flavonoids, etc.) antioxidants; and metal chelating proteins to prevent Fenton and Haber-Weiss chemistry]. In addition, a major part of the free radical theory involves the damaging role of reactive oxygen species and various toxins on mitochondria. These lead to numerous mitochondrial DNA mutations which result in a progressive reduction in energy output, significantly below that needed in body tissues. This can result in various signs of aging, such as loss of memory, hearing, vision, and stamina. Oxidative stress also inactivates critical enzymes and other proteins. In addition to these factors, caloric restriction is the only known method that increases the life span of rodents; studies currently underway suggest that this also applies to primates, and presumably to humans. Certainly, oxidative stress plays an important role here, although other, as yet unknown, factors are also presumably involved. Exactly how the other major theories (i.e., immune, neuroendocrine, somatic mutation, error catastrophe) control aging is more difficult to define. The immune and neuroendocrine systems clearly deteriorate with age. (ABSTRACT TRUNCATED)
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PMID:The biochemistry of aging. 1104 Sep 57

ADVERSE EFFECTS OF OXYGEN: Adverse effect of oxygen on anaerobes implies oxidation of the basic cell constituents NAD(P)H, thiols, iron-sulphur proteins, pteridines and others) and inactivation of the essential components of the active site of enzymes. Oxygen can also adversely affect the aerobes, especially if long-term influence is taken into consideration, while exposition to high-pressure oxygen causes considerable damages. Direct influence of oxygen on aerobes due to slow and limited enzyme inactivation (for example glutamate decarboxylase) and small number of affected "targets" is not responsible for total adverse effects of oxygen. Even in 1954 it was supposed that oxygen free radicals are the most responsible for the adverse effects of oxygen. ATMOSPHERIC (TRIPLET) OXYGEN: Electron configuration of triplet oxygen explains its reactivity since it is a biradical. The reactions of oxygen with non-radicals are possible with participation of transition metals (except zinc), while its reactivity is much more expressed in case of reactions with other radical species. ACTIVE OXYGEN: More reactive forms of oxygen, known as singlet oxygen, can be generated by an input of energy to triplet oxygen. Singlet-oxygen is obtained mainly by photoexcitation in the presence of initiators (methylene blue, chlorophyll etc.) and as a product of reactions of ozone with certain biomolecules. REDUCED FORMS OF OXYGEN: If a single electron is added to the triplet oxygen, it must enter one of the antibonding molecular orbitals and produce the superoxide radical--(O2.-). Addition of one more electron produces peroxide ion--O2(2-), which forms hydro peroxide in presence of H+, the most common two-electron reduction product of oxygen in biological systems. The four-reduction product of oxygen in biological systems is water. SUPEROXIDE RADICAL: The in vivo production of superoxide radical is possible in many different ways mentioned in this paper. This radical species is unstable in water solutions because of dismutation reaction leading to non-enzymic generation of hydroperoxide. The most reactive radical species--hydroxyl radical is produced from hydro peroxide by Fenton or Haber-Weiss reactions in the presence of catalytic transition metals (iron or copper). HYDROXYL RADICAL: Hydroxyl radicals are the most reactive radical species. The way of their generation has been shown in detail in this paper with special emphasis given to Fenton and Haber-Weiss reactions, that is, transition metals (iron and copper) as catalizators for these reactions. The reactivity of hydroxyl radical can be recognized by monitoring the second-order rate constants for reactions of the hydroxyl radical with some organic compounds in aqueous solution presented in this paper. Although the number of compounds that can be affected and damaged by hydroxyl radicals is great, until now, attention has been paid mostly to investigation of attacks of these radical species on lipids, proteins and DNA. LIPID PEROXIDATION: Radicals react with lipids and cause oxidative destruction of unsaturated, that is, polyunsaturated fatty acids, known as lipid peroxidation. Both lipids in biological systems and lipids as food constituents are submitted to this process. Lipid peroxidation is a chain reaction and its mechanism has been shown in detail in this paper. Lipid peroxidation in cells leads to direct damage of cell membranes with indirect damages of other cell constituents, caused by reactivity of secondary products of this reaction, aldehydes. This complex reaction is responsible for damages of many tissues and progress of some diseases (atherosclerosis). OXIDATIVE STRESS: Protection of an organism from oxygen free radicals implies activity of enzymatic (catalase, SOD, glutathione peroxidase, glutathione reductase etc.) and nonenzymatic (vitamin E. vitamin C. glutathione, uric acid etc.) systems of protection. Disturbance of the balance between production of oxygen free radicals (or some other radical species) and activity of antioxidative system of protection causes the so called oxidative stress. An organism can tolerate a mild oxidative stress but a higher disturbance between the production of free radicals and the activity of the antioxidative protection results in lipid protein and DNA as well as numerous diseases.
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PMID:[Free oxygen radiacals and kidney diseases--part I]. 1132 Jul 27

The present study describes the effects of several high-fat low-cholesterol antiatherogenic diets on the hepatic lipid peroxidation and hepatic antioxidant systems in apolipoprotein E-deficient mice. Eighty mice were distributed into five groups and fed with regular mouse chow or chow supplemented with coconut, palm, olive and sunflower seed oils. After ten weeks, they were sacrificed and the livers were removed so that lipid peroxidation and alpha-tocopherol concentrations, and superoxide dismutase, glutathione peroxidase and glutathione reductase activities could be measured. The size of the atherosclerotic lesions in the aortas was also measured. Results showed that the diets supplemented with olive oil, palm oil or sunflower seed oil significantly decreased the size of the lesion. However, there was an association between those mice that were on diets supplemented with palm or coconut oils and a significant increase in hepatic lipid peroxidation. This association was not found in animals fed with olive or sunflower seed oils, the diets with the highest content of vitamin E. The dietary content of vitamin E was significantly correlated (r = 0.98; p < 0.05) with the hepatic concentration of this compound. Our study suggests that the high content of vitamin E in olive oil or sunflower seed oil may protect from the undesirable hepatotoxic effects of high-fat diets in apo E-deficient mice and that this should be taken into account when these diets are used to prevent atherosclerosis.
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PMID:Effects of high-fat, low-cholesterol diets on hepatic lipid peroxidation and antioxidants in apolipoprotein E-deficient mice. 1133 Aug 32

The effects of 17beta-estradiol (17beta-E(2)) or the phytoestrogen naringenin on spontaneous atherosclerosis were studied in 36 ovariectomized homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits receiving a semisynthetic control diet; this diet added 0.0040% 17beta-E(2;) or 0.20% naringenin, for 16 weeks. The uterine weight was increased (P < 0.001) and the concentration of estrogen receptor alpha was decreased (P < 0.001) in the 17beta-E(2) group compared with the controls. Total plasma cholesterol and triglycerides were not different from those in the controls. In lipoproteins, HDL cholesterol was increased (P < 0.01), and LDL triglyceride and IDL triglyceride were lowered (P < 0.05). The oxidation (as concentration of malondialdehyde) was increased in LDL (P < 0.05) but not in plasma. The cholesterol accumulation was decreased (P < 0.05) in the ascending aorta and in the total aorta but the ratio of intima to media and area of intima in ascending, thoracic, and abdominal aorta were not significantly different. In the naringenin group the only differences, compared with the control group, were increased HDL cholesterol (P < 0.001) and decreased activity of glutathione reductase (P < 0.05). In conclusion, 17beta-E(2), but not naringenin, attenuated aortic cholesterol accumulation independently of plasma and LDL cholesterol. Further, these results support previously suggested pro-oxidant ability of 17beta-E(2) toward LDL and a possible connection between the pro-oxidant nature of 17beta-E(2) and its antiatherogenic effect.
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PMID:17beta-Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits. 1135 91


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