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)

The effect of intraperitoneal injections of potassium chromate on prevention and regression of atherosclerosis was observed in New Zealand White rabbits. In rabbits fed a 1% cholesterol diet for 90 days, potassium chromate injection was not associated with a significant difference in weight, serum cholesterol, total cholesterol content per 8.5 cm aorta, cholesterol content per gram of aorta or percent intima covered with plaque compared to controls. Similarly, significant differences were not seen in rabbits fed a 1% cholesterol diet for 90 days followed by 60 days of potassium chromate or distilled water injections and a standard diet. These results are in keeping with recent studies suggesting a more limited role for chromium in a variety of lipid-related disorders.
Atherosclerosis 1986 Jan
PMID:Effects of potassium chromate on atherosclerosis prevention and regression in rabbits. 394 21

Rabbits fed on a 1% cholesterol diet for 30 days were injected daily with potassium chromate for a further 60 days. A 50% reduction in aortic intimal plaque area and in aortic total cholesterol content was observed. Control rabbits treated with chromium showed a significant increase in the chromium concentration of their aortas, liver and kidneys but not of the myocardium. Cholesterol-fed rabbits treated with chromium showed a significant increase in chromium concentrations in the liver and kidneys only. Serum cholesterol levels were consistently lower in the chromium-treated animals, although the differences did not reach significant levels.
Atherosclerosis 1982 Feb
PMID:The effect of chromium on cholesterol-induced atherosclerosis in rabbits. 706 83

Eight rabbits, fed on a 1% cholesterol diet for 30 days, were injected daily with potassium chromate for a further 60 days. A 50% reduction in aortic intimal plaque area and in aortic total cholesterol content was observed. However, although levels of serum cholesterol and triglycerides were consistently lower and levels of high density lipoprotein fractions consistently higher in the chromium-treated as compared to the control rabbits, these differences did not reach statistical significance. A further 6 rabbits were injected with potassium chromate and fed on a 1% cholesterol diet for 12 weeks. Mean aortic cholesterol content (+/-SEM) was 40.23 mg/10 cm aortic length (+/-7.50) as compared to 66.24 mg/10 cm (+/- 7.89) in a control group (P less than 0.05), whereas the area of aortic intima covered by macroscopic plaques was 67.5% (+/-2.79) and 81.1% (+/-3.14) (P less than 0.01) respectively.
Atherosclerosis 1982 Apr
PMID:The action of chromium on serum lipids and on atherosclerosis in cholesterol-fed rabbits. 707 1

Oxidation of LDL is thought to contribute to the early stages of atherogenesis. Because myeloperoxidase is present in atherosclerotic lesions and can produce the strong oxidant hypochlorous acid (HOCl), which converts LDL into its high-uptake atherogenic form in vitro, we raised polyclonal and monoclonal antibodies (MoAbs) against HOCl-modified LDL (HOCl-LDL). Characterization of the polyclonal anti-human HOCl-LDL Abs showed that they cross-reacted strongly with 4-hydroxynonenal-, malondialdehyde-, and Cu(2+)-oxidized LDL. Similarly, polyclonal and some monoclonal Abs against aldehyde- and Cu(2+)-modified LDL cross-reacted with HOCl-LDL. In contrast to the polyclonal Abs, two selected hybridoma cell line supernatants containing MoAbs raised against HOCl-LDL (MoAb-A and MoAb-B) did not cross-react with either native LDL or aldehyde- or Cu(2+)-modified LDL. MoAb-A (clone 1B10A11, subtype IgG1 kappa) recognized an epitope that appeared to be specific for HOCl-LDL and depended on the tertiary structure of the (lipo)protein, as judged by a lack of cross-reactivity with HOCl-modified human and bovine serum albumin and a loss of reactivity associated with lipoprotein denaturation. MoAb-B (clone 2D10G9, subtype IgG2b kappa), on the other hand, gave identical titration curves with HOCl-LDL and HOCl-modified albumins, suggesting that this antibody recognized epitopes that are commonly generated on proteins that have been oxidized with HOCl. Thus, MoAb-A and MoAb-B may be useful tools for the investigation of a possible role for HOCl-mediated damage to (lipo)proteins in atherosclerosis and other inflammatory diseases.
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PMID:Immunologic detection and measurement of hypochlorite-modified LDL with specific monoclonal antibodies. 754 Dec 96

Oxidatively modified lipoproteins have been implicated in atherogenesis, but the mechanisms that promote oxidation in vivo have not been identified. Myeloperoxidase, a heme protein secreted by activated macrophages, generates reactive intermediates that oxidize lipoproteins in vitro. To explore the potential role of myeloperoxidase in the development of atherosclerosis, we determined whether the enzyme was present in surgically excised human vascular tissue. In detergent extracts of atherosclerotic arteries subjected to Western blotting, a rabbit polyclonal antibody monospecific for myeloperoxidase detected a 56-kD protein, the predicted molecular mass of the heavy subunit. Both the immunoreactive protein and authentic myeloperoxidase bound to a lectin-affinity column; after elution with methyl mannoside their apparent molecular masses were indistinguishable by nondenaturing size-exclusion chromatography. Peroxidase activity in detergent extracts of atherosclerotic lesions likewise bound to a lectin column and eluted with methyl mannoside. Moreover, eluted peroxidase generated the cytotoxic oxidant hypochlorous acid (HOCl), indicating that enzymatically active myeloperoxidase was present in lesions. Patterns of immunostaining of arterial tissue with antihuman myeloperoxidase antibodies were similar to those produced by an antimacrophage antibody, and were especially prominent in the shoulder region of transitional lesions. Intense foci of myeloperoxidase immunostaining also appeared adjacent to cholesterol clefts in lipid-rich regions of advanced atherosclerotic lesions. These findings identify myeloperoxidase as a component of human vascular lesions. Because this heme protein can generate reactive species that damage lipids and proteins, myeloperoxidase may contribute to atherogenesis by catalyzing oxidative reactions in the vascular wall.
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PMID:Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. 804 Feb 85

Oxidation of low density lipoprotein (LDL) may be of critical importance in triggering the pathological events of atherosclerosis. Myeloperoxidase, a heme protein secreted by phagocytes, is a potent catalyst for LDL oxidation in vitro, and active enzyme is present in human atherosclerotic lesions. We have explored the possibility that reactive intermediates generated by myeloperoxidase target LDL cholesterol for oxidation. LDL exposed to the myeloperoxidase-H2O2-Cl- system at acidic pH yielded a family of chlorinated sterols. The products were identified by mass spectrometry as a novel dichlorinated sterol, cholesterol alpha-chlorohydrin (6beta-chlorocholestane-(3beta,5alpha)-diol), cholesterol beta-chlorohydrin (5alpha-chlorocholestane-(3beta, 6beta)-diol), and a structurally related cholesterol chlorohydrin. Oxidation of LDL cholesterol by myeloperoxidase required H2O2 and Cl-, suggesting that hypochlorous acid (HOCl) was an intermediate in the reaction. However, HOCl failed to generate chlorinated sterols under chloride-free conditions. Since HOCl is in equilibrium with molecular chlorine (Cl2) through a reaction which requires Cl- and H+, this raised the possibility that Cl2 was the actual chlorinating intermediate. Consonant with this hypothesis, HOCl oxidized LDL cholesterol in the presence of Cl- and at acidic pH. Moreover, in the absence of Cl- and at neutral pH, Cl2 generated the same family of chlorinated sterols as the myeloperoxidase-H2O2-Cl- system. Finally, direct addition of Cl2 to the double bond of cholesterol accounts for dichlorinated sterol formation by myeloperoxidase. Collectively, these results indicate that Cl2 derived from HOCl is the chlorinating intermediate in the oxidation of cholesterol by myeloperoxidase. Our observations suggest that Cl2 generation in acidic compartments may constitute one pathway for oxidation of LDL cholesterol in the artery wall.
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PMID:Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols. 879 98

Free radicals, such as superoxide, hydroxyl and nitric oxide, and other "reactive species", such as hydrogen peroxide, hypochlorous acid and peroxynitrite, are formed in vivo. Some of these molecules, e.g. superoxide and nitric oxide, can be physiologically useful, but they can also cause damage under certain circumstances. Excess production of reactive oxygen or nitrogen species (ROS, RNS), their production in inappropriate relative amounts (especially superoxide and NO) or deficiencies in antioxidant defences may result in pathological stress to cells and tissues. This oxidative stress can have multiple effects. It can induce defence systems, and render tissues more resistant to subsequent insult. If oxidative stress is excessive or if defence and repair responses are inadequate, cell injury can be caused by such mechanisms as oxidative damage to essential proteins, lipid peroxidation, DNA strand breakage and base modification, and rises in the concentration of intracellular "free" Ca(2+). Considerable evidence supports the view that oxidative damage involving both ROS and RNS is an important contributor to the development of atherosclerosis. Peroxynitrite (derived by reaction of superoxide with nitric oxide) and transition metal ions (perhaps released by injury to the vessel wall) may contribute to lipid peroxidation in atherosclerotic lesions.
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PMID:Blood radicals: reactive nitrogen species, reactive oxygen species, transition metal ions, and the vascular system. 886 Apr 19

During inflammatory disorders, some proteases and very reactive oxygen metabolites are produced by activated phagocytic cells. These proteases and oxidants are involved in many diseases like tissue injury or atherosclerosis. It was shown in vitro that diltiazem, a calcium channel blocker, had antielastase and antioxidant properties. This drug inhibited the release of elastase by neutrophils in a dose dependent manner when these cells were stimulated by phorbol-myristate-acetate (PMA) or by formyl-methionyl-leucylphenylalanine (fMLP) with an IC50 of 144.5 microM, and 132.8 microM, respectively. Towards the oxidants, the 50% inhibitory concentrations (IC50) of diltiazem are 422 microM, 138 microM and 165 microM for superoxide anion, hypochlorous acid and hydroxyl radical production by PMA stimulated human neutrophils, respectively. In the case of fMLP stimulated human neutrophils, the IC50 for superoxide anion is 78 microM. When human neutrophils were stimulated by dioctanoylglycerol (DiC8) or by calcium ionophore (Ca.I), the IC50 for superoxide anion were 175.5 microM and 186 microM, respectively. When human neutrophils were stimulated by opsonized zymosan (OZ), diltiazem did not show an inhibition of superoxide production in a dose dependent manner. This drug did not act by scavenging elastase or oxidants as demonstrated by cell free models. A mechanism of elastase and oxygen metabolites inhibition by diltiazem has been considered specially toward the mobilization of cytosolic calcium and an inhibition of protein kinase C cannot be excluded. The results suggest that diltiazem might contribute to attenuate the development and the progression of atheroma where oxidants and elastase have been implicated.
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PMID:Effects of calcium antagonist diltiazem on leukocyte elastase and on reactive oxygen species production in human neutrophils. 887 26

Many lines of evidence implicate oxidation of low density lipoprotein (LDL) in the pathogenesis of atherosclerosis, a chronic inflammatory disease. The physiologically relevant mechanisms have not been identified, but phagocytic white cells may play an important role because macrophage-rich lesions characterize the disorder. Recent studies have shown that myeloperoxidase, a heme enzyme secreted only by phagocytes, is present in human atherosclerotic tissue. The enzyme is a potent catalyst of LDL oxidation in vitro, it co-localizes with macrophages in lesions, and it generates products that are detectable in atherosclerotic plaque. These findings suggest that myeloperoxidase may promote LDL oxidation in the artery wall. This article reviews the enzyme's ability to generate a range of oxidants, including tyrosyl radical, reactive aldehydes, hypochlorous acid and molecular chlorine. These products have the potential to damage host molecules as well as microbes, suggesting a mechanism that may contribute to atherosclerotic vascular disease.
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PMID:Pathways for oxidation of low density lipoprotein by myeloperoxidase: tyrosyl radical, reactive aldehydes, hypochlorous acid and molecular chlorine. 925 96

Oxidatively damaged LDL may play a critical role in the pathogenesis of atherosclerotic vascular disease. Several pathways promote LDL oxidation in vitro but the physiologically relevant mechanisms have proven difficult to identify. Detection of stable compounds that result from specific reaction pathways has provided the first insights into the mechanism of oxidative damage in the human artery wall. Mass spectrometric analysis of protein oxidation products isolated from atherosclerotic tissue implicate tyrosyl radical, reactive nitrogen intermediates and hypochlorous acid in LDL oxidation and lesion formation in vivo. Hypochlorous acid is only generated by the phagocytic enzyme myeloperoxidase, which can also generate tyrosyl radical and reactive nitrogen intermediates. Chiral phase high-pressure liquid chromatography analysis of lipid oxidation products suggests that cellular lipoxygenases may also play a role at certain stages. In contrast, LDL isolated from atherosclerotic tissue is not enriched in protein oxidation products characteristic of free metal ions, which are the most widely studied in vitro model of LDL oxidation. These observations provide the first direct chemical evidence for reaction pathways that promote LDL oxidation in human atherosclerosis.
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PMID:Mechanisms of oxidative damage of low density lipoprotein in human atherosclerosis. 933 50


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