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)

Nitric oxide (NO) has been shown to inhibit platelet adhesion and aggregation, but there are no reports on its interaction with the coagulation system. We investigated the effect of the L-arginine analogues, N-nitro-L-arginine (LNA), N(G)-nitro-L-arginine methyl ester (L-NAME), and N(G)-monomethyl-L arginine (L-NMMA), competitive inhibitors of NO production, on endothelial-surface heparan sulfate. Addition of LNA to porcine aortic endothelial cells reduced 125I-labeled antithrombin III binding to the cell surface heparan sulfate in a dose- and time-dependent fashion. Significant inhibition was observed with 1 mM LNA, and the maximal suppression (-50% of control) occurred at 10 mM LNA after 12 h. L-NAME (1 mM) and L-NMMA (1 mM) also significantly inhibited the antithrombin III binding. The iron chelator desferrioxamine significantly prevented the reduction of antithrombin III binding to LNA-treated cells. We further investigated the effect of L-NAME on intracellular oxidative stress of endothelial cells using a hydroperoxide-sensitive fluorochrome, carboxy-dichloro-dihydrofluorescein diacetate bisacetoxymethyl ester probe, and revealed that inhibition of NO synthesis by L-NAME led to a marked increase in intracellular oxidative stress. These results demonstrated that the prolonged inhibition of NO synthesis in porcine aortic endothelial cells decreases the expression of anticoagulant heparan sulfate on endothelial cells through the increase in intracellular oxidative stress, perhaps comprising another mechanism by which NO affects the coagulation system in the vasculature.
Atherosclerosis 1997 Nov
PMID:Endothelial-derived nitric oxide preserves anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. 939 68

It has been suggested that iron plays an important role in the pathogenesis of atherosclerosis, primarily by acting as a catalyst for the atherogenic modification of LDL. Although some epidemiological data suggest that high stored iron levels are an independent risk factor for coronary artery disease and that iron has been detected in both early and advanced atherosclerotic lesions, the evidence is often contradictory and inconclusive. We used the New Zealand White rabbit to investigate the effects of iron overload (FeO) and iron deficiency (FeD) on atherosclerosis. Groups of 7 rabbits were either iron loaded by injections of iron dextran (FeO group), iron depleted by phlebotomy (FeD group), or given injections of saline (control group) for a total of 9 weeks. All rabbits were fed a chow diet containing 1% (wt/wt) cholesterol for the last 6 weeks of the study. Iron and antioxidant status and cholesterol levels were assayed in plasma before cholesterol feeding (week 3) and at the time that the rabbits were killed (week 9). In addition, the susceptibility of LDL to oxidation was measured and pathological examination of the aortic arch and thoracic aorta performed at the end of the study. FeD significantly decreased the levels of blood hemoglobin, serum iron, and transferrin saturation compared with controls. Conversely, FeO significantly increased transferrin Fe saturation. FeO but not FeD decreased plasma cholesterol levels compared with control animals both before (P < .05) and after (P = .055) cholesterol feeding. Neither FeO nor FeD had a significant effect on the levels of antioxidants and lipid peroxidation products in plasma and aortic tissue or on the susceptibility of LDL to ex-vivo oxidation. FeO significantly decreased aortic arch lesion formation by 56% compared with controls (P < .05), whereas FeD had no significant effect. These results indicate that in this animal model, FeO decreases rather than increases atherosclerosis, likely because iron dextran exerts a hypocholesterolemic effect. Our data do not support the hypotheses that elevation of Fe stores increases or that a reduction of Fe stores by phlebotomy decreases the risk of coronary artery disease.
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PMID:Effect of iron overload and iron deficiency on atherosclerosis in the hypercholesterolemic rabbit. 940 37

Various researchers have observed a higher risk for atherosclerosis when body iron concentration is elevated. The exact mechanism, however, is not known, but probably occurs catalytically via iron. Whether or not body iron concentration has an effect on plasma lipoproteins is also unknown. The aim of this study was to investigate whether or not ferritin concentration within the normal range correlate with LDL-cholesterol (an atherosclerotic risk factor), HDL-cholesterol, apoB, triglyceride and the mobility of LDL particles. Blood was drawn from healthy female volunteers and the above parameters measured. LDL-cholesterol, apoB and the electrophoretic mobility of LDL particles were elevated with increasing ferritin concentrations. Both modified or oxidized LDL and elevated LDL concentration are regarded as risks for atherosclerosis and ischemic heart disease, suggesting that higher body iron is important in this process.
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PMID:Influence of ferritin levels on LDL cholesterol concentration in women. 946 28

Low-density lipoprotein (LDL) cholesterol participates in the atherosclerotic process only after oxidative modification (o-LDL). Persons with elevated body iron concentrations are at higher risk of atherosclerosis. Iron in vitro is capable of oxidizing LDL, but it is unknown whether or not high dietary iron concentrations alter LDL in vivo. The aim of this study was, therefore, to investigate (i) whether dietary iron concentrations cause LDL-cholesterol oxidation and (ii) whether antioxidants can prevent such changes. Rats received diets differing only in iron concentration: 35 mg/kg, 150 mg/kg or 300 mg/kg diet. A LDL-VLDL particle was isolated and the following parameters measured: malondialdehyde and lipid hydroperoxide concentrations (as an indication for lipid peroxidation); alpha-tocopherol and retinol concentrations (as antioxidants); protein sulfhydryl and carbonyl concentrations (as an indication of protein modification); agarose gel electrophoresis and cholesterol/protein ratio. Dietary iron increased LDL-VLDL lipid peroxidation (malondialdehyde and lipid hydroperoxide concentrations), protein modification (sulfhydryl concentration), agarose migration distance and band width as well as cholesterol/protein ratio. Increased quantities of dietary iron led to a higher degree of oxidative change in LDL-VLDL. Lipid peroxidation, as well as protein modification, occurred, suggesting apoB changes. This was probably due to diminished antioxidant concentrations of alpha-tocopherol and beta-carotene. Antioxidant supplementation (alpha-tocopherol and beta-carotene), however, prevented all the above changes and could be helpful in the prevention of atherosclerosis.
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PMID:Dietary iron concentration alters LDL oxidatively. The effect of antioxidants. 952 56

Excess iron has been postulated as a risk factor for coronary artery disease (CAD) because of its presence in atherosclerotic lesions, its ability to oxidize low density lipoprotein cholesterol (LDLc), and its promotion of oxygen reperfusion damage after an ischemic event. Whether iron, indirectly measured by its storage protein ferritin and its transport protein transferrin, is related to CAD was examined in a consecutive series of white male (n = 457) and female (n = 114) cardiac patients. Atherosclerosis measures were analyzed in patients grouped by tertiles of ferritin. A similar analysis was done with tertiles of transferrin. Contrary to expectations, men in the third tertile of ferritin had a smaller mean number of stenoses than men in the two lower tertiles (4.9 versus 5.6 and 5.9; P = 0.027); otherwise, there were no statistically significant differences in either number of lesions or extent of arterial narrowing based on tertiles of either measure. Separate multiple logistic regression models with age, fibrinogen, LDLc and triglycerides as covariates provided no evidence that ferritin (odds ratio = 0.88 with 95% C.I. = 0.72-1.07 for men and odds ratio = 0.79 with 95% C.I. = 0.54-1.16 for women) or transferrin (odds ratio = 0.60 with 95% C.I. = 0.31-1.16 for men and odds ratio = 1.33 with 95% C.I. 0.52-3.42 for women) were important correlates of the presence of atherosclerosis in this study.
Atherosclerosis 1998 Feb
PMID:Iron measures in coronary angiography patients. 954 94

Acrolein (CH2==CH---CHO) is known as a ubiquitous pollutant in the environment. Here we show that this notorious aldehyde is not just a pollutant, but also a lipid peroxidation product that could be ubiquitously generated in biological systems. Upon incubation with BSA, acrolein was rapidly incorporated into the protein and generated the protein-linked carbonyl derivative, a putative marker of oxidatively modified proteins under oxidative stress. To verify the presence of protein-bound acrolein in vivo, the mAb (mAb5F6) against the acrolein-modified keyhole limpet hemocyanin was raised. It was found that the acrolein-lysine adduct, Nepsilon-(3-formyl-3, 4-dehydropiperidino)lysine, constitutes an epitope of the antibody. Immunohistochemical analysis of atherosclerotic lesions from a human aorta demonstrated that antigenic materials recognized by mAb5F6 indeed constituted the lesions, in which intense positivity was associated primarily with macrophage-derived foam cells and the thickening neointima of arterial walls. The observations that (i) oxidative modification of low-density lipoprotein with Cu2+ generated the acrolein-low-density lipoprotein adducts and (ii) the iron-catalyzed oxidation of arachidonate in the presence of protein resulted in the formation of antigenic materials suggested that polyunsaturated fatty acids are sources of acrolein that cause the production of protein-bound acrolein. These data suggest that the protein-bound acrolein represents potential markers of oxidative stress and long-term damage to protein in aging, atherosclerosis, and diabetes.
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PMID:Protein-bound acrolein: potential markers for oxidative stress. 956 Jan 97

The uptake of modified low density lipoprotein via the macrophage scavenger receptor (MSR) results in the formation of lipid-laden foam cells during atherosclerosis. Because increased oxidative stress has been implicated in the pathogenesis of atherosclerosis, the role of reactive oxygen species on the activity and expression of MSR was investigated. The uptake of acetylated low density lipoprotein and the levels of MSR-I mRNA were inhibited by treatment with the oxygen radical scavengers 2,2,6, 6-tetramethylpiperidine-N-oxyl, dimethylthiourea or sodium benzoate, or the iron chelator deferoxamine. Dimethylthiourea or benzoate also decreased the levels of MSR-I mRNA in the presence of the transcription inhibitor actinomycin D. These results indicate that hydroxyl radicals produced from superoxide anions and hydrogen peroxide in the presence of free iron, contribute to an increased MSR activity by stabilizing MSR-I mRNA. Several sources of reactive oxygen species are involved as inhibition of MSR activity and levels of MSR-I mRNA occurred in the presence of rotenone, a mitochondrial complex I inhibitor, or acetovanillone, a NADPH oxidase inhibitor. The (oxidative) stress responsive nuclear factor kappaB is not involved as inhibitors of its activation remained without significant inhibition. In contrast to MSR-I, the levels of MSR-II mRNA, which is formed by alternative splicing of the same gene transcript, were largely unaffected by the inhibitors of reactive oxygen species formation and activity. The present results suggest that oxidant stress contributes to an increased activity of MSR by stabilizing MSR-I mRNA.
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PMID:Reactive oxygen species regulate macrophage scavenger receptor type I, but not type II, in the human monocytic cell line THP-1. 961 11

The presence of ceroid, a complex of protein associated with oxidized lipids, is commonly observed in human atherosclerotic lesions. When the human aortic walls were examined by Perls' staining, it was found that the iron deposits were evident in aortas with atherosclerosis. The extent of iron deposition was associated with the severity of the lesion. Furthermore, the iron deposits appeared to be colocalized with ceroids either extracellularly or intracellularly in foam cell-like macrophages or smooth muscle cells. Electron microscopy and X-ray microanalysis revealed that some of the extracellular iron aggregates were present within the ceroids. Likewise, some of the subcellular iron aggregates were found to be located near the lipid droplets or within the ceroids of foam cells. Collectively, these observations support the theory that the lipid oxidation occurring in lipid-laden cells of aortic lesions is facilitated by iron-overload in these cells.
Atherosclerosis 1998 Jun
PMID:Colocalization of iron and ceroid in human atherosclerotic lesions. 969 Sep 11

Body iron status has been implicated in atherosclerotic cardiovascular disease. The main hypothesis was that high iron status was associated with increased oxidation of LDL. The associations of serum ferritin (a marker of iron status) and dietary iron intake with the susceptibility of LDL to in vitro oxidation (lag phase) and autoantibodies against MDA-modified LDL (two markers of oxidation stress) were examined among 281 men and 192 women with a mean age of 59 years (S.D. = 5) who participated in the Atherosclerosis Risk in Communities (ARIC) Study visit 2 in 1990 through 1992. Lag phase duration and the autoantibodies against MDA-modified LDL were weakly correlated with each other (r = 0.19, P = 0.001 in men; r = 0.15, P = 0.03 in women). In linear regression analysis adjusting for age, field center, blood storage time, and carotid atherosclerosis case-control status, there was no association between ferritin level and the lag-phase, or between ferritin level and autoantibodies against MDA-modified LDL in either sex. Further adjustment for traditional cardiovascular risk factors (smoking, vitamin supplement use, body mass index, LDL cholesterol, hypertension and diabetes) did not alter these null results. Ferritin was significantly and positively correlated with body mass index in both sexes (r = 0.21 among men and r = 0.22 among women) and with the waist-to-hip ratio among women (r = 0.26). In addition, among women, ferritin was positively correlated with orosomucoid (r = 0.24) and with sialic acid (r = 0.19). Dietary iron was not associated with the parameters of LDL oxidation or with ferritin level. These findings do not support a role of body iron stores in promoting oxidation of LDL.
Atherosclerosis 1998 Jul
PMID:Lack of association between ferritin level and measures of LDL oxidation: the ARIC study. Atherosclerosis Risk in Communities. 969 7

(E)-4-Hydroxy-2-nonenal (HNE) is a highly reactive product of the oxidation of low density lipoprotein (LDL) which increases the platelet aggregation response to various agonists. HNE formation was increased during the enhanced platelet aggregation to thrombin, ADP. A23187 and epinephrine in the presence of LDL. The increase in platelet aggregation and HNE formation by LDL was inhibited by superoxide dismutase and catalase, suggesting superoxide and hydrogen peroxide produced by platelets during aggregation may be at least partly responsible. The responsiveness of platelets to LDL and the accompanying HNE formation was increased further in the presence of ferrous ion. The effect of ferrous ion on both platelet responses and HNE formation was decreased by superoxide dismutase, catalase and the antioxidants dipyridamole and probucol implicating platelet-derived free radicals. Ferrous ion caused an increase in the release of arachidonic acid from platelet membrane phospholipids in the presence of LDL which was probably caused by increased HNE production. The results suggest iron could increase platelet reactivity at sites of vascular injury by increasing HNE formation and promote the development of atherosclerotic lesions.
Atherosclerosis 1998 Sep
PMID:The role of (E)-4-hydroxy-2-nonenal in platelet activation by low density lipoprotein and iron. 973 21


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