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)

There is increasing evidence that oxidative modification of low density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Subjects with familial hypercholesterolaemia (FH) have elevated concentrations of LDL and develop premature atherosclerosis. The aim of the study was to determine whether the susceptibility of LDL to in vitro oxidation is increased in FH subjects. LDL was isolated from 15 FH homozygotes (mean age +/- SD, 19 +/- 10 years; mean LDL-cholesterol 16.86 +/- 3.55 mmol/l), 15 FH heterozygotes (38 +/- 13 years; LDL-cholesterol 5.58 +/- 1.78 mmol/l) and 15 normocholesterolaemic subjects (31 +/- 8 years; LDL-cholesterol 3.07 +/- 0.77 mmol/l). Susceptibility of LDL to in vitro copper-mediated oxidation was assessed by measuring conjugated diene production at 234 nm, the lag phase being a measure of the resistance of LDL to oxidation. Unexpectedly, the mean duration of the lag phase was 2.2 fold longer in the FH homozygotes (123.8 +/- 45.0 min) and 1.75-fold longer in the FH heterozygotes (99.9 +/- 40.6 min) than in the controls (57.1 +/- 27.9 min; P < 0.0001). Serum and LDL vitamin E levels were higher in the FH patient, but not when expressed relative to LDL-cholesterol concentration. There was also no correlation between LDL vitamin E concentration and duration of the lag phase. LDL bulk rather than the susceptibility of LDL to oxidation is probably the more important factor for the initiation and progression of atherosclerosis in FH patients.
Atherosclerosis 1995 May
PMID:Susceptibility of low density lipoprotein to oxidation in familial hypercholesterolaemia. 766 91

It has been generally accepted that oxidized low density lipoprotein (LDL) plays an important role in atherogenesis. However, oxidized LDL was not detected in patients' blood and the extent of LDL oxidation in vivo is unknown. We have suggested that LDL oxidation may lead to a formation of covalent links between lipids and apolipoprotein B. LDL were oxidized by copper ions, 2,2'-azobis-(2-aminopropane hydrochloride), sodium hypochlorite or by incubation with macrophages. Oxidized LDL were delipidated by repeated extraction with organic solvents. After mild alkaline hydrolysis protein-bound sterols were identified colorimetrically and by high-performance liquid chromatography. Protein-bound phospholipid residues were detected by nuclear magnetic resonance and colorimetric determination of phosphate. Using radiolabeled lipids it was also shown that free and esterified cholesterol, phospholipids, as well as triglyceride and free fatty acid residues can form covalent bonds with apolipoprotein B. The ability of lipids to bind to apolipoprotein B correlates with the degree of unsaturation of their fatty acids and depends on the nature of polar head of phospholipids. When LDL were oxidized with copper ions, the content of protein-bound lipids increased gradually up to 24 h of incubation, while the levels of conjugated dienes, hydroperoxides and thiobarbituric acid-reactive substances changed in varying manners. It has been demonstrated that the content of protein-bound sterols in multiple-modified desialylated LDL of patients with coronary atherosclerosis is higher than that in native LDL. Our results suggest that the level of protein-bound lipids may be a marker of LDL oxidation and can be used to evaluate the association of lipoprotein oxidation and atherogenesis.
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PMID:Apolipoprotein B-bound lipids as a marker for evaluation of low density lipoprotein oxidation in vivo. 767 72

Serum copper concentration increases significantly (p < 0.01) in rats with experimental atherosclerosis compared to a control group. The serum zinc, the zinc, and copper concentration in abdominal aorta and in liver decreases significantly (p < 0.05) compared to the control group. Administration of copper sulfate for 100 d in these animals induces a significant increase of serum copper (p < 0.01), decrease of serum cholesterol (p < 0.05) and increase of liver copper concentration as compared with the group fed only a high cholesterol diet. In the aorta of these animals the copper concentration increases and edema and lipid infiltration are considerably less than in the group of animals fed only a high lipid diet.
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PMID:Effect of copper sulfate on experimental atherosclerosis. 769 Nov 31

Contact to artificial surfaces during hemodialysis activates leukocytes, which then form oxidized arachidonic acid products and free radicals. This might promote the oxidative modification of low-density lipoproteins (LDL) that play a key role in the initiation of atherosclerosis. Thus, leukocyte activation could specifically contribute to the high mortality from atherosclerotic complications on long-term hemodialysis. Therefore monitored LDL and high-density lipoprotein (HDL) resistance to copper-stimulated oxidation in patients with end-stage renal disease on maintenance hemodialysis with cellulose acetate or polysulfone membranes (n = 12), in patients with chronic renal failure (n = 13) and in healthy controls (n = 12). Six of the dialysis patients were restudied during a single cuprophane dialysis. Circulating leukocytes were reversibly reduced early in hemodialysis with cellulose acetate (minimum, 83.6% +/- 7.4% of baseline values at 30 minutes after dialysis start), polysulfone (minimum, 80.4% +/- 10.5% at 15 minutes; P < 0.05) and cuprophane (minimum, 24.5% +/- 8.5% at 60 minutes; P < 0.0001). Despite the leukocyte activation, LDL oxidation lag time was not shortened in comparison with healthy controls and was even prolonged at the end of cellulose acetate (P < 0.05) and cuprophane (P < 0.05) dialysis. HDL oxidation lag time increased (12.6% +/- 0.9%; P < 0.0001) 15 to 60 minutes after start of hemodialysis and returned to predialysis values thereafter. In patients with chronic renal failure, the lag time of HDL oxidation was significantly prolonged (13.34 minutes +/- 0.9) compared with healthy controls (10.91 +/- 2.0 minutes; P < 0.01) as well as compared with the dialysis patients at baseline (9.9 minutes +/- 1.4; P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preserved antioxidative defense of lipoproteins in renal failure and during hemodialysis. 770 51

Tea polyphenols (flavan-3-ol derivatives) suppressed the oxidative modification of low density lipoprotein (LDL) which is assumed to be an important step in the pathogenesis of atherosclerosis lesions. Inhibitory experiments on the oxidative impairment of porcine serum LDL by flavan-3-ols were carried out by incubating them at 37 degrees C in the presence of 5 microM Cu2+. The oxidation of LDL was monitored either by an absorption increase at 234 nm due to the conjugated diene formation, or the formation of hydroperoxides and thiobarbituric acid reactive substances (TBARS). It was found that the oxidation was strongly inhibited by various flavan-3-ols, and a lag time over 100 min appeared, depending on the types of flavan-3-ols used. The activities based on the prolongation of the lag time were in the order of (-)-epigallocatechin (EGC) < (+)-catechin (C) < (-)-epicatechin (EC) < (-)-epicatechingallate (ECG) < (-)-epigallocatechingallate (EGCG). IC50 of flavan-3-ols on Cu2+ mediated hydroperoxides and TBARS formation of LDL were 0.90, 0.95 microM for ECG and 2.38, 2.74 microM for EGC, respectively. It was found that the Cu2+ mediated cholesterol ester degradation in LDL was almost completely inhibited by 5.0 microM C or EGCG. Cu2+ mediated apolipoprotein B-100 fragmentation was also inhibited (up to 60%) in the presence of C or EGCG.
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PMID:The inhibitory effects of tea polyphenols (flavan-3-ol derivatives) on Cu2+ mediated oxidative modification of low density lipoprotein. 773 96

Cigarette smokers have reduced levels of plasma high density lipoprotein (HDL) compared to nonsmokers and are at risk of premature cardiovascular disease. Previous work from this laboratory has shown that exposure of human plasma to gas-phase cigarette smoke (CS) inhibited the activity of lecithin:cholesterol acyltransferase (LCAT), the enzyme that catalyzes the formation of cholesteryl ester in HDL and thereby promotes HDL maturation. As CS contains free radicals that could potentially oxidize plasma lipoproteins, we examined the involvement of lipid peroxidation in LCAT inhibition. Results obtained with CS were compared with those obtained by initiating lipid peroxidation with copper ions. Exposure of dialyzed human plasma to an equivalent of one-eighth of a cigarette at 15-min intervals resulted in a progressive loss of LCAT activity (50 and 90% reductions by 1 and 6 h, respectively). A similar pattern of LCAT inhibition was produced with copper (0.5 mM) where 50 and 97% reductions were observed at 1 and 6 h, respectively. To determine whether LCAT inhibition was related to lipid peroxidation, lipoprotein fractions corresponding to VLDL-IDL, LDL, and HDL were isolated from plasma exposed to CS or copper and analyzed for changes in TBARS, the polyunsaturated fatty acid arachidonate relative to palmitate (20:4/16:0 ratio), and vitamin E concentrations. Exposure of plasma for 6 h to CS had no effect on the levels of TBARS and 20:4/16:0 ratio; however, 6 h copper treatment (0.5 mM) caused a 3.0-, 4.0-, and 1.4-fold increase in TBARS and a 17, 25, and 13% reduction in the 20:4/16:0 ratio in VLDL-IDL, LDL, and HDL fractions, respectively. In addition, a complete depletion of lipoprotein vitamin E was observed with CS, whereas copper decreased vitamin E levels by approximately 50% in each fraction. Supplementation of plasma with either vitamin C (85 microM) or butylated hydroxytoluene (BHT, 0.45 mM) was unable to protect LCAT from CS. In contrast, BHT completely protected LCAT activity from inhibition by copper. We conclude that unlike copper, CS-induced inhibition of plasma LCAT activity was unrelated to free radical-induced lipid peroxidation. The inhibition of LCAT activity by cigarette smoke may contribute to the development of atherosclerosis by impairing HDL metabolism and the reverse cholesterol transport process.
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PMID:Copper and gas-phase cigarette smoke inhibit plasma lecithin:cholesterol acyltransferase activity by different mechanisms. 775 20

Oxidatively modified LDL (oLDL) is thought to play a key role in the pathogenesis of atherosclerosis. We have studied Cu(2+)-induced peroxidation reactions of LDL and have elucidated the sequence of events which subsequently occur within LDL particles by 1H-NMR spectroscopy. Studies of chloroform/methanol extracts show that LDL arachidonate is oxidised by Cu2+ at a higher rate and to a greater extent than linoleate, giving isomeric hydroperoxides with predominantly trans,trans double-bonds, whilst only cis,trans isomers were detected as intrinsic hydroperoxides in control LDL samples. These intrinsic hydroperoxides were not degraded during peroxidation, suggesting that they are not involved in the initiation of Cu(2+)-induced peroxidation. Aldehydes arising from the decomposition of hydroperoxides were also detected, as well as saturated fatty acids which were released into the external aqueous medium. Decomposition pathways of the two major isomeric hydroperoxides are discussed. Cu(2+)-induced oxidation of LDL cholesterol appears to occur only after hydroperoxide breakdown, with esterified cholesterol being oxidised to a greater extent than free cholesterol. Phospholipid hydrolysis appeared to parallel the peroxidation of arachidonic acid, and the released lysophosphatidylcholine may become associated with apoB. These results suggest that hydroperoxide breakdown (probably in phospholipids) may be a key event in the peroxidation process, leading to the oxidation of cholesterol and propagation into the core of LDL.
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PMID:Copper-induced LDL peroxidation investigated by 1H-NMR spectroscopy. 776 90

Excess vascular oxidative stress and the local formation of oxidized LDL (ox-LDL) have been implicated in the development of impaired endothelium-dependent arterial relaxation in hypercholesterolemia and atherosclerosis. Dietary antioxidants limit LDL oxidation in vitro and treatment of cholesterol-fed rabbits with dietary antioxidants preserves endothelium-derived relaxing factor (EDRF) action. To investigate the mechanism(s) responsible for these observations, we examined EDRF action, vascular oxidative stress, and antioxidant protection in male New Zealand White rabbits using four dietary treatments. Animals consumed standard chow (chow group) or chow supplemented with: (a) 0.5% cholesterol (0.5% cholesterol group); (b) 1% cholesterol (1% cholesterol group); or (c) 1% cholesterol and 1% probucol (probucol group). After 28 d of dietary treatment, segments of thoracic aorta from the 0.5 and 1% cholesterol groups demonstrated impairment of acetylcholine-mediated endothelium-dependent arterial relaxation compared to chow-fed animals (57 +/- 11% and 45 +/- 9% vs 78 +/- 3%, respectively; P < 0.05). In contrast, vessels from the probucol group demonstrated normal relaxation to acetylcholine (83 +/- 5%). Plasma cholesterol levels and the extent of atherosclerosis were similar among all cholesterol-fed groups. Probucol treatment was associated a threefold increase in LDL resistance to copper-induced oxidative modification (P < 0.05) and a reduction in tissue lipid peroxidation (as assessed by thiobarbituric acid-reactive substances; P < 0.05) compared to animals fed cholesterol alone. Most importantly, both of these changes were strongly correlated with preserved EDRF action. Moreover, cholesterol feeding was associated with a dose-dependent increase in vascular superoxide generation and lysophosphatidylcholine content, both of which were prevented by probucol treatment. From these findings, we conclude that probucol, a lipid-soluble antioxidant, preserves EDRF action in cholesterol-fed rabbits in association with limiting vascular oxidative stress and superoxide generation.
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PMID:Dietary probucol preserves endothelial function in cholesterol-fed rabbits by limiting vascular oxidative stress and superoxide generation. 776 97

Oxidative modification of low density lipoprotein (LDL) by cigarette smoke has been suggested in several recent studies. To characterize possible modification of LDL by cigarette smoke extract (CSE), we incubated LDL with CSE either in the presence or absence of the chemical pro-oxidants, cupric chloride or 2,2'-azo-bis(2-amidinopropane) hydrochloride (AAPH). Surprisingly, CSE inhibited oxidative modification of LDL induced by either copper or AAPH. Under such oxidant stress conditions, CSE inhibited formation of thiobarbituric acid-reactive substances and also inhibited the increased agarose gel electrophoretic mobility of LDL in a dose-response manner. In addition, CSE prevented degradation of phosphatidylcholine to lysophosphatidylcholine and also fragmentation of the apolipoprotein B-100 moiety of LDL. Finally, CSE inhibited loss of immunoreactivity of the treated LDL with a murine monoclonal antibody against human apolipoprotein B-100. On the other hand, at higher concentrations, CSE per se was still able to cause structural changes in LDL. After incubation with CSE for 24 h, LDL showed a slight increase in agarose gel electrophoretic mobility, a slight loss of immunoreactivity with monoclonal antibody, and a marked increase in protein carbonyl formation. Lipid peroxidation did not appear to be involved in the modification of LDL caused by CSE. It is suggested that reactive aldehydes present in cigarette smoke may cause direct chemical modification of LDL. Furthermore, the free radical-scavenging potential of the tar fraction of cigarette smoke may be responsible for the apparent antioxidant properties of CSE against LDL oxidation.
Atherosclerosis 1995 Jan 20
PMID:Cigarette smoke extract inhibits oxidative modification of low density lipoprotein. 777 77

The inhibition of low density lipoprotein (LDL) oxidation has been postulated as one mechanism by which antioxidants may prevent the development of atherosclerosis. Available data on the ability of beta-carotene to inhibit LDL oxidation are conflicting. We examined the role of in vivo and in vitro supplementation with beta-carotene on metal ion-dependent (cupric ions, Cu2+) and metal ion-independent (2,2'-azobis[2-amidinopropane]dihydrochloride, AAPH) oxidation of LDL as measured by the formation of conjugated dienes (absorbance at 234 nm). Sixteen subjects were supplemented with 50-100 mg of beta-carotene on alternate days for 3 weeks following a week-long loading dose of 100 mg/day. Plasma beta-carotene levels rose 5.5-fold, while LDL beta-carotene levels rose 8.5-fold. Oxidation of LDL by Cu2+ or AAPH was not significantly delayed after in vivo supplementation with beta-carotene compared with baseline. For AAPH, the lag phase (in minutes) was 75 +/- 8 at baseline and 83 +/- 14 after supplementation (P = 0.07). For Cu2+, the lag phase was 172 +/- 41 at baseline and decreased to 130 +/- 24 after supplementation (P < 0.01). Similarly, no protective effect against Cu(2+)-induced oxidation was observed when beta-carotene was added to LDL in vitro. Supplementation of plasma with beta-carotene in vitro prior to LDL isolation also did not enhance LDL's resistance to Cu(2+)- or AAPH-induced oxidation, despite a 5-fold increase in LDL beta-carotene levels over vehicle control.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Jan 20
PMID:Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation. 777 78


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