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)

Macrophages play a part in pathogenesis of atherosclerosis, oxidizing LDL-cholesterol and transforming themselves in foam cells and producing free radicals of oxygen that may also oxidize LDL-cholesterol. HMG-CoA reductase inhibitors are very efficient in long-term control of atherogenesis acting by different mechanisms not fully established. Thus, we investigated the in vitro influence of pravastatin on phagocytosis and hydrogen peroxide production by monocytes of healthy individuals. Phagocytosis of Saccharomyces erevisiae by peripheral blood monocytes of 20 healthy individuals was assessed in the absence or presence of pravastatin. Hydrogen peroxide production was assessed based on the horseradish peroxidase-dependent oxidation of phenol red method. Pravastatin had no influence on phagocytosis through scavenger receptors, while it decreased by 20% the mean+/-SD phagocytic index of monocytes through complement receptors, from 141+/-77 to 113+/-56 (p=0.017), due to a decrease in the number of particles ingested by monocytes, from 2.1+/-0.5 to 1.7+/-0.3 (p=0.003). This statin also decreased the baseline production of hydrogen peroxide, by 7.7%, from 0.098+/-0.013 to 0.091+/-0.013 (OD by 2x10(5) monocytes per hour) (p=0.025). Pravastatin was able to decrease the phagocytosis through complement receptors and caused a decrease in the production of hydrogen peroxide by monocytes. It is possible this statin may directly inhibit the development of atherosclerotic plaque and its instability dependent on phagocytosis and the presence of reactive species of oxygen.
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PMID:Effects of pravastatin on the in vitro phagocytic function and hydrogen peroxide production by monocytes of healthy individuals. 1633 13

Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. Cellular changes show that oxidative stress is a condition that precedes the appearance of the hallmark pathologies of the disease, neurofibrillary tangles and senile plaques. The aim of this article is to analyze the different biomarkers of oxidative stress in Alzheimer patients, in different stages of the illness, and compare the results with a control group. A nutritional evaluation was carried out, including anthropometric and biological measures and a 3 day dietary record. The concentration of substances which react to thiobarbituric acid (TBARS) was measured as a marker of the degree of peroxidation using the HPLC method. The oxidation of proteins was analyzed by measuring the carbonyl groups in plasma. In addition, measurements were made of the total antioxidant activity in plasma and the activity of endogenous antioxidant enzymes such as gluthatione peroxidase, gluthatione reductase and superoxide dismutase. The total antioxidant plasmatic status of the patients with Alzheimer both in light-moderate phase and in advanced phase was lower than in the control. No significant differences were observed between the different stages of the disease in protein oxidation levels. Peroxidation was higher in patients in the advanced stage of the disease than in the control group. However, no significant differences were observed between the different stages of the disease. In this preliminary study, it was observed that Alzheimer patients in the light-moderate stage already present oxidative stress levels above those of the control group.
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PMID:Oxidative stress in Alzheimer patients in different stages of the disease. 1661 Oct 85

Diabetes mellitus is characterized by fasting hyperglycemia, with both type 1 and type 2 diabetes. Persons are also known to be prone to develop complications related to elevated blood glucose concentrations, including atherosclerosis, retinal damage, cataract, and neuropathy. Hyperglycemia may also result in increased production of the reactive oxygen species within numerous biochemical pathways that have the potential to initiate changes in endothelial function. This article demonstrates the presence of lipid peroxidation products in the red cell membranes of type 2 diabetic patients compared to the normal subjects. These membranes are more susceptible to exogenous oxidative stress than those of normal healthy individuals. Significantly higher activities of antioxidant enzymes, namely, serum peroxidase, superoxide dismutase (SOD), and catalase (CAT) were found in type 2 diabetic patients as compared to control. This study led us to conclude that elevated levels of glucose induce oxidative stress that is ultimately reflected by the increased malondialdehyde (MDA) levels in erythrocyte ghost membranes of diabetic patients. Hyperglycemia also induced an increase in antioxidant enzymes and a relationship seems to exist between diabetic complications and elevated levels of these enzymes. It is suggested that these antioxidant enzymes may be considered as markers for vascular injury.
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PMID:Lipid peroxidation and serum antioxidant enzymes in patients with type 2 diabetes mellitus. 1715 23

Liposomal glutathione, but not the control liposomes (with no glutathione), dose-dependently inhibited copper ion-induced low density lipoprotein (LDL) and HDL oxidation. As peroxidase activity was found to be present in both LDL and HDL, it has contributed to the anti-oxidative effects of liposomal glutathione. In-vitro, no significant effect of liposomal glutathione on J774 A.1 macrophage cell-line oxidative stress and on cellular cholesterol metabolism was observed. In contrast, in the atherosclerotic apolipoprotein E-deficient (E(0)) mice, consumption of liposomal glutathione (12.5 or 50mg/kg/day, for 2 months), but not control liposomes, resulted in a significant reduction in the serum susceptibility to AAPH-induced oxidation by 33%. Liposomal glutathione (50mg/kg/day) consumption also resulted in an increment (by 12%) in the mice peritoneal macrophages (MPM) glutathione content, paralleled by a significant reduction in total cellular lipid peroxides content (by 40%), compared to placebo-treated mice MPM. MPM paraoxonase 2 activity was significantly increased by 27% and by 121%, after liposomal glutathione consumption (12.5 or 50mg/kg/day, respectively). Analyses of cellular cholesterol fluxes revealed that, liposomal glutathione (12.5mg/kg/day) consumption, decreased the extent of oxidized-LDL (Ox-LDL) uptake by 17% and the cellular cholesterol biosynthesis rate, by 34%, and stimulated HDL-induced macrophage cholesterol efflux, by 19%. Most important, a significant reduction in macrophage cholesterol mass (by 24%), and in the atherosclerotic lesion area (by 30%) was noted. We thus conclude that liposomal glutathione possesses anti-oxidative and anti-atherogenic properties towards lipoproteins and macrophages, leading to attenuation of atherosclerosis development.
Atherosclerosis 2007 Dec
PMID:Anti-oxidant and anti-atherogenic properties of liposomal glutathione: studies in vitro, and in the atherosclerotic apolipoprotein E-deficient mice. 1758 83

Myeloperoxidase (MPO) catalyzes the formation of potent oxidants that have been implicated in the pathogenesis of various diseases including atherosclerosis, asthma, arthritis, and cancer. Melatonin plays an important part in the regulation of various body functions including circadian sleep rhythms, blood pressure, oncogenesis, retinal function, seasonal reproduction, and immunity. Here, we demonstrate that melatonin serves as a potent inhibitor of MPO under physiological-like conditions. In the presence of chloride (Cl-), melatonin inactivated MPO at two points in the classic peroxidase cycle through binding to MPO to form an inactive complex, melatonin-MPO-Cl, and accelerating MPO compound II formation, an inactive form of MPO. Inactivation of MPO was mirrored by the direct conversion of MPO-Fe(III) to MPO compound II without any sign of compound I accumulation. This behavior indicates that melatonin binding modulates the formation of MPO intermediates and their decay rates. The Cl- presence enhanced the affinity of MPO toward melatonin, which switches the enzyme activity from peroxidation to catalase-like activity. In the absence of Cl-, melatonin served as a 1e- substrate for MPO compound I, but at higher concentration it limited the reaction by its dissociation from the corresponding complex. Importantly, melatonin-dependent inhibition of MPO occurred with a wide range of concentrations that span various physiological and supplemental ranges. Thus, the interplay between MPO and melatonin may have a broader implication in the function of several biological systems. This dual regulation by melatonin is unique and represents a new means through which melatonin can control MPO and its downstream inflammatory pathways.
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PMID:Melatonin is a potent inhibitor for myeloperoxidase. 1823 95

Oxidative modification of low-density lipoprotein (LDL) represents an important factor in atherogenesis. In the present study, we have investigated the antioxidant capability of diphenyl diselenide (PhSe)(2), a simple organoseleno compound, against copper (Cu2+) and peroxyl radical-induced human LDL oxidation in vitro. In initial studies using human serum, (PhSe)(2) caused a dose-dependent inhibition of Cu(2+)-induced lipid peroxidation, which was correlated to thiol consumption. (PhSe)(2) increased lipid peroxidation lag phase and decreased lipid peroxidation rate in isolated human LDL, evaluated by measuring both conjugated diene (CD) and thiobarbituric acid reactive substances (TBARS) levels. Consistent with these observations, (PhSe)(2) showed a marked inhibitory effect on 2,2-azobis(2-amidinopropane dihydrochloride) (AAPH)-induced oxidation of LDL or parinaric acid (PnA) incorporated into LDL. (PhSe)(2) also displayed a dose-dependent protective effect against Cu(2+)-induced lipid peroxidation in rat aortic slices. Interestingly, besides the antioxidant effects of (PhSe)(2) toward the lipid moieties of LDL, which was related to its thiol-peroxidase activity, protein moieties from human isolated LDL were also protected against Cu(2+)-induced oxidation. The results presented herein are the first to show that (i) (PhSe)(2) inhibits lipid peroxidation in human isolated LDL in vitro, (ii) this phenomenon is related to its thiol-peroxidase activity, and (iii) this chalcogen also prevents the oxidation of protein moieties of human LDL. Taken together, such data render (PhSe)(2) a promising molecule for pharmacological studies with respect to the atherogenic process.
Atherosclerosis 2008 Nov
PMID:Diphenyl diselenide, a simple glutathione peroxidase mimetic, inhibits human LDL oxidation in vitro. 1844 6

The accelerated atherosclerosis that occurs in some patients with systemic lupus erythematosus (SLE) has a complex pathogenesis, including alterations in lipids, inflammation and the immune system. In this article, we review the evidence that peroxidase-related alteration of normal, protective high-density lipoprotein (HDL) converts them to pro-inflammatory HDL (piHDL), characterized by lower content of the cholesterol transport lipoprotein ApoA1 and impaired function of the antioxidant enzyme paroxonase, which prevents oxidation of low-density lipoprotein (LDL). Forty-five per cent of women with SLE have piHDL compared with 20% of patients with rheumatoid arthritis and 4% of healthy controls. The presence of piHDL increases risk for coronary artery events and carotid artery plaque. Another result of lipid oxidation in patients with SLE is generation of highly oxidized LDL and phospholipids (PL), probably stimulating antibodies to OxPL phospholipids. These antibodies along with promoting thrombosis also interfere with deposits of Annexin V onto endothelial cells, which probably promote increased instability of atherosclerotic plaque. Thus, piHDL and anti-OxPL promote plaque formation, plaque instability and thrombosis, accounting for some of the large increase in atherosclerosis and coronary artery events in SLE.
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PMID:Atherosclerosis and systemic lupus erythematosus: the role of altered lipids and of autoantibodies. 1849 Apr 9

Oxidative stress has been linked to the origin and progression of cardiovascular diseases. Nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase is a multi-component, NADPH-dependent enzyme that generates superoxide anion in the presence of molecular oxygen. The enzyme has been identified and characterized in all 3 vascular wall cell types and represents the major source of reactive oxygen species (ROS) production in the vascular wall. Inhibition of NADPH oxidase activation appears to suppress the sequence of cellular events that leads to a variety of cardiovascular diseases, including atherosclerosis. The naturally occurring methoxyphenol apocynin has been found to inhibit NADPH oxidase upon activation by peroxidases (e.g. soybean peroxidase, myeloperoxidase) or ROS under mild reaction conditions. Upon peroxidase-catalyzed activation, the apocynin oxidation products act to block the assembly and activation of NADPH oxidase. Although the mechanism of inhibition of NADPH oxidase remains largely unknown, apocynin's high effectiveness and low toxicity makes it a promising lead compound in the development of new therapeutic agents for cardiovascular diseases.
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PMID:The role of the methoxyphenol apocynin, a vascular NADPH oxidase inhibitor, as a chemopreventative agent in the potential treatment of cardiovascular diseases. 1867 60

The effects of chitin-glucan (CG) on early atherosclerosis, cardiac production of superoxide anion, and hepatic antioxidant enzymes were studied in an animal model of atherosclerosis. Three groups of 12 hamsters were fed an atherogenic diet for 12 weeks. They received by gavage either water (control group) or CG in water at a dose of 21.4 mg/kg BW x d-1 of chitin-glucan (CG ld) or 42.8 mg/kg BW x d-1 (GG hd). CG did not affect plasma cholesterol but lowered triglycerides. It also strongly reduced the area of aortic fatty streak deposition by 87-97%, cardiac production of superoxide anion by 25% and liver MDA by 77-85%, and enhanced liver superoxide dismutase activity by 7-45% and glutathionne peroxidase activity by 38-120%. These findings support the view that chronic consumption of chitin-glucan has potential beneficial effects with respect to the development of atherosclerosis. The underlying mechanism is related mainly to improving the antioxidant status.
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PMID:Fungal chitin-glucan from Aspergillus niger efficiently reduces aortic fatty streak accumulation in the high-fat fed hamster, an animal model of nutritionally induced atherosclerosis. 1915 4

There is an emerging and significant body of research that suggests that MPO (myeloperoxidase) may be a critical mediator in dysfunctional lipoprotein formation and, hence, atherogenic initiation and progression. MPO is a haem peroxidase found in leucocytes and is abundant in macrophages surrounding atherosclerotic lesions. Several lines of evidence support the role of MPO-mediated carbamylation of proteins in atherogenesis. The generic mechanism of MPO-mediated protein carbamylation has been elucidated recently and has been identified as a potentially crucial pathway that links smoking, inflammation and atherogenesis. HDL (high-density lipoprotein) exerts a physiologically beneficial effect of reducing arterial cholesterol deposition; however, there are considerable gaps in current understanding of the molecular basis of dysfunctional HDL formation. Especially deserving of attention is a contextual understanding of dysfunctional pro-atherogenic HDL formation in light of inflammatory changes in atheroma. The present review is especially timely in light of the solved structures of nascent and discoidal HDL and integrates the biochemical significance of MPO carbamylation in the context of these structures. Various avenues of experimental investigation are explored which will be crucial in understanding the vascular consequences of dysfunctional HDL formation and the identification of novel mechanistic pathways in vascular disease. It is anticipated that further knowledge on the intricacies of dysfunctional HDL formation, potentially by an MPO-driven pathway, will lead to considerable progress in identifying novel drug targets for atherosclerosis and characterization of the primary atherogenic process.
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PMID:Myeloperoxidase-mediated lipoprotein carbamylation as a mechanistic pathway for atherosclerotic vascular disease. 1932 51


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