Oxidative Susceptibility Of Low Density Lipoprotein Research Articles

Sesame lignans reduce LDL oxidative susceptibility by downregulating the platelet-activating factor acetylhydrolase.

Low-density lipoprotein (LDL) oxidative susceptibility is recognized as a risk factor for atherosclerosis. We previously reported that the ingestion of a supplement containing sesame lignans (sesamin/episesamin) for 4 weeks reduced LDL oxidative susceptibility in humans. To elucidate the mechanisms underlying this observation, 12-week-old New Zealand White rabbits were fed a fat/cholesterol-enriched diet (100 g/day) for 6 weeks followed by oral administration of vehicle (control) or sesame lignans (50 mg/kg) for 4 weeks with the fat/cholesterol-enriched diet. The results showed that the ingestion of sesame lignans prolonged LDL oxidation lag time, regardless of the existence of the anti-oxidative catechol metabolite of sesamin/episesamin in LDL. Plasma platelet-activating factor acetylhydrolase (PAF-AH) activity was significantly reduced by sesame lignans. The prolongation of LDL oxidation lag time was abolished by the addition of a PAF-AH inhibitor. The expression level of pro-inflammatory cytokines and macrophage infiltration observed in the liver following the feeding of the fat/cholesterol-enriched diet were also significantly reduced by sesame lignans. These results indicate that sesame lignans reduce LDL oxidative susceptibility by downregulating plasma PAF-AH activity via the reduction of inflammation in the liver induced by fat/cholesterol-enriched diets.

Pine bark extract prevents low-density lipoprotein oxidation and regulates monocytic expression of antioxidant enzymes

Polyphenols are widely distributed in leaves, seeds, bark, and flowers and considered to have beneficial effects on cardiovascular health. We hypothesized that the potent antioxidant properties of pine bark extract (PBE) are exerted by its ability to scavenge free radicals and induce antioxidant enzymes. Therefore, we investigated the effects of PBE on low-density lipoprotein (LDL) oxidation and the antioxidant defense system in monocytes. Oxidative susceptibility of LDL was determined by lag time assay in vitro and by using a human umbilical vein endothelial cell–mediated oxidation model. THP-1 monocytic cells were treated with PBE, and the expression of antioxidant enzymes was measured by real-time polymerase chain reaction and Western blot. Pine bark extract showed radical scavenging ability and significantly inhibited free radical-induced and endothelial cell-mediated LDL oxidation in vitro. Pine bark extract treatment resulted in increases in the expressions of antioxidant enzymes, glutathione peroxidase-1, catalase, and heme oxygenase-1 in THP-1 cells. In addition, PBE induced nuclear factor-erythroid-2–related factor 2 activation, which was accompanied by the activation of extracellular signal-regulated kinase and Akt despite a down-regulation of reactive oxygen species. After the monocyte investigations, we further examined the antioxidant effect after the intake of PBE by 10 healthy male volunteers. Pine bark extract significantly prolonged the lag time of LDL oxidation. Based on our findings, it appears that PBE enhances the antioxidant defense capacity of LDL and monocytes and may play a preventive role in atherosclerosis progression.

English

The modified low-density lipoprotein (LDL; glycated and oxidized) is more atherogenic and are poorly recognized by LDL receptor. In the present study, an attempt has been made to evaluate the effects of Triphala on LDL modification in experimentally treated rats and in human LDL. The effect of ethanolic extract of Triphala on LDL oxidation susceptibility in high fat diet fed and STZ induced rats was evaluated. The inhibitory effect of Triphala on LDL oxidation and glycation was investigated using copper and glucose induced human LDL, respectively in vitro. The co-presence of Triphala extract significantly increased lag phase and minimized the conjugated dienes formation in dose dependent manner. Copper mediated LDL oxidation was characterized by elevated indices of thiobarbituric acid reactive substance (TBARS), whereas co-presence of Triphala extract significantly minimized the production of TBARS. The results of this investigation shows that Triphala probably with their antioxidant properties inhibited LDL glycation and oxidation and provide scientific reasons regarding the possible medical benefits of using Triphala to prevent diabetic and cardiovascular complications.   Key words: Triphala, low-density lipoprotein (LDL) oxidation, LDL glycation, high fat diet, streptozotocin (STZ).

A fibre cocktail of fenugreek, guar gum and wheat bran reduces oxidative modification of LDL induced by an atherogenic diet in rats

LDL (low-density lipoprotein) oxidation is a key trigger factor for the development of atherosclerosis. Relatively few studies exist on the impact of dietary fibre on LDL oxidation. This study was undertaken to evaluate the influence of a novel fibre mix of fenugreek seed powder, guar gum and wheat bran (Fibernat) on LDL oxidation induced by an atherogenic diet. Male Wistar albino rats were administered one of the following diets: (1) a control diet that was fibre-free (Group I); (2) an atherogenic diet containing 1.5% cholesterol and 0.1% cholic acid (Group II) or (3) an atherogenic diet supplemented with Fibernat (Group III). Peroxidative changes in low-density lipoprotein (LDL) and the oxidative susceptibility of LDL and the LDL + VLDL (very low-density lipoprotein) fraction were determined. As a corollary to the oxidative modification theory, the titer of autoantibodies to oxidised LDL (oxLDL) was determined at various time points of the study. In addition, plasma homocysteine (tHcy) and lipoprotein (Lp (a)), apolipoprotein (apoB), cholesterol, triglyceride, phospholipid and alpha-tocopherol content of LDL were determined. A decrease in malonaldehyde (MDA) content (p<0.05) and relative electrophoretic mobility (REM) of LDL was observed in the group III rats as compared to the group II rats. An increase in lag time to oxidation (p<0.01) and decrease in maximum oxidation (p<0.01) and oxidation rate (p<0.01) were observed in the LDL + VLDL fraction of group III rats. In group II rats, formation of autoantibodies to oxLDL occurred at an earlier time point and at levels greater than in the group III rats. Fibernat, had a sparing effect on LDL alpha-tocopherol, which was about 51% higher in the group III rats than in the group II rats; apo B content of LDL was reduced by 37.6% in group III rats. LDL of group III rats displayed a decrease in free and ester cholesterol (p<0.01) as compared to that of group II. A decrease in plasma homocysteine (p<0.01) and an increase in GSH (p<0.05) were also observed in group III rats when compared with that of group II. Fibernat administration appears to combat oxidative stress resulting in a trend to lower oxidative modification of LDL. In addition, the cholesterol and apo B content of LDL were reduced significantly with a sparing effect on LDL alpha-tocopherol. This novel fibre preparation could be an effective diet therapy and therefore needs further investigation.

Acarbose ameliorates atherogenecity of low-density lipoprotein in patients with impaired glucose tolerance

Acarbose, an α-glucosidase inhibitor, is administered to control blood glucose levels. The drug also reduces the risk of cardiovascular disease, but the underlying mechanism is still to be elucidated. We therefore hypothesized that treatment with acarbose ameliorates the atherogenecity of low-density lipoprotein (LDL), a key molecule in atherogenesis. Patients with impaired glucose tolerance were or were not treated with acarbose (acarbose-treated group [n = 20] and control group [n = 20], respectively) for 3 months under dietary therapy. The oxidative susceptibility of LDL was determined by measuring lag time for the formation of dienes in the presence of CuSO 4. The lag time was significantly longer in the acarbose-treated group than in the control group before treatment. Moreover, the density gradient lipoprotein separation and disk polyacrylamide gel electrophoresis analyses showed that acarbose reduced the amount of small dense LDL, a more atherogenic and oxidatively susceptible form of LDL. We also found that the fatty acid composition of LDL changed after the treatment: polyunsaturated ( ω-3) fatty acid, a beneficial substance for preventing cardiovascular disease, was significantly increased, whereas saturated fatty acids and triglyceride were decreased in the LDL of the acarbose-treated group. The present findings suggest that acarbose treatment reduces the risk of cardiovascular diseases by ameliorating the atherogenecity of LDL.

The Melbourne Atherosclerosis Vitamin E Trial (MAVET): a study of high dose vitamin E in smokers

Our aim was to evaluate whether vitamin E (500 IU) slowed the progression of carotid atherosclerosis in a population of chronic smokers over 4 years as measured by ultrasound determination of carotid intima-media thickness (IMT) and systemic arterial compliance (SAC). The Melbourne Atherosclerosis Vitamin E Trial (MAVET) was a randomized, double-blind, placebo-controlled trial in which 409 male and female smokers aged 55 years and over were randomized to receive 500 IU per day of natural vitamin E or placebo. The primary endpoint was progression of carotid atherosclerosis determined by intima-media thickness of the right common carotid artery. Secondary outcomes were change in systemic arterial compliance and low-density lipoprotein (LDL) oxidative susceptibility over time. The mean increase in intima-media thickness over time in the vitamin E group was 0.0041 mm/year faster than placebo (95% confidence interval -0.0021 to 0.0102 mm/year, P = 0.20). Similarly, a non-significant difference between vitamin E and placebo was found for rate of change in systemic arterial compliance (P = 0.11). Vitamin E supplementation did, however, significantly reduce LDL oxidative susceptibility (P < 0.001). Vitamin E supplementation is ineffective in reducing the progression of carotid atherosclerosis as measured by intima-media thickness in chronic smokers. This finding extends our knowledge of lack of effectiveness of vitamin E supplementation in populations with high oxidant stress.

Soy protein with and without isoflavones fails to substantially increase postprandial antioxidant capacity

Five methods for the assessment of antioxidant capacity [whole plasma conjugated diene formation, low-density lipoprotein oxidation susceptibility, ferric-reducing ability of plasma, oxygen radical absorbance capacity and perchloric-acid-treated oxygen radical absorbance capacity (PCA-ORAC)] were used in a randomized, double blind, crossover study to determine the acute postprandial antioxidant protection imparted by the isoflavone component of soy. On separate days, 16 subjects consumed one of three isocaloric shakes containing 25g of protein in the form of soy, with 107 mg of total aglycone units of isoflavones, soy with trace isoflavones (<4 mg) or total milk protein. Blood was collected at baseline, 4h, 6h and 8h after consumption. Antioxidant capacity, serum isoflavone levels, fat-soluble antioxidants and plasma vitamin C levels were evaluated. Repeated measures analysis of variance showed no significant differences ( P=.05) within treatments over time in four of five antioxidant capacity measurements. Significant differences over time between the soy with trace isoflavones and the total milk protein group were observed using the PCA-ORAC assay. It can be concluded that, on an acute basis, a significant increase in serum antioxidant capacity is not detectable following consumption of soy protein.

We-P14:407 Effect of coffee on the oxidative susceptibility of low-density lipoprotein

We-P14:407 Effect of coffee on the oxidative susceptibility of low-density lipoprotein

Ex vivo measures of LDL oxidative susceptibility predict carotid artery disease

Aim: The purpose of the study was to assess whether ex vivo measures of low-density lipoprotein (LDL) oxidation improved prediction of carotid artery disease (CAAD) case-control status compared to standard lipid and smoking measures. Methods: One hundred and forty cases with a high degree of carotid artery stenosis aged 40–83 years and an equal number of controls without stenosis or other vascular disease were matched by censored age within 2 years. Matched logistic regression evaluated the significance of copper-induced oxidative measures with and without covariates. The relationship of LDL oxidation measures with statin use and current smoking was also evaluated. Results: Logistic regression demonstrated a significant effect of the three correlated measures of oxidative susceptibility (lag time, oxidation rate and maximal rate of oxidation) separately on disease prediction (all p < 0.05). These oxidative measures remained significant predictors of case-control status when other cardiovascular disease predictors (age; LDL-C, HDL-C and ApoAI levels; current smoking, ever smoking and pack-years smoked) were jointly considered. This relationship was not attributable to the effects of statin use on LDL oxidation. Conclusions: Ex vivo measures of oxidation improved the prediction of carotid artery disease status, suggesting that this is an important determinant of atherosclerotic risk in this older population.

Small low-density lipoprotein particles and endothelium-dependent vasodilation in postmenopausal women

Low concentrations of estrogen may decrease endothelial function in postmenopausal women. Elevated plasma triglycerides after menopause are frequently associated with a small, dense low-density lipoprotein (LDL) phenotype. Small LDL particles that are more susceptible to oxidation can also inhibit endothelium-dependent vasodilation. The purpose of the present study was to investigate whether hypertriglyceridemia-induced small LDL particles are associated with endothelial dysfunction in postmenopausal women. We studied 15 premenopausal and 41 postmenopausal women. Postmenopausal subjects were divided into those with LDL subclass pattern A (large particles) and those with pattern B (small particles). Plasma lipids, hormones, and diameter and oxidative susceptibility of LDL were measured. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation (NID). FMD in both postmenopausal groups was significantly lower than in premenopausal women. FMD in subjects with pattern B was significantly smaller than in those with pattern A (4.9 ± 1.9% versus 8.8 ± 3.6%). NID did not differ significantly among the groups. Plasma triglyceride concentrations were higher, lag time for LDL oxidation was shortened, and LDL-derived thiobarbituric acid-reactive substance (TBARS) concentrations were significantly greater in subjects with pattern B than in premenopausal or pattern A subjects. LDL diameter correlated negatively with plasma triglycerides ( r = −0.51) or LDL-derived TBARS ( r = −0.44) and positively with LDL-lag time ( r = 0.66). FMD correlated negatively with LDL-derived TBARS ( r = −0.36) and positively with LDL diameter ( r = 0.44) or LDL-lag time ( r = 0.43). Vascular endothelial dysfunction may be associated with elevated triglyceride-induced small LDL particles that have enhanced oxidative susceptibility in postmenopausal women.

LDL particle size and lipid composition are risk factors for microalbuminuria in normotensive and normocholesterolemic patients with type 2 diabetes

The study was to evaluate the influence of particle size and lipid composition of low-density lipoprotein (LDL) on urinary albumin excretion and oxidative susceptibility of LDL, and to define association between LDL particle size and α-tocopherol content in LDL from normotensive and normocholesterolemic patients with type 2 diabetes. Twenty-three patients with type 2 diabetes (13 males, 10 females) were studied, and none of these patients had hypertension, hypercholesterolemia and overt proteinuria. The baseline body mass index of all patients was less than 28 kg/m 2. All patients were hospitalized in Hirosaki University Hospital and took dietary therapy whose total intake was restricted to less than 30 kcal/kg of ideal body weight for 3 weeks. Their plasma glucose levels were controlled within fasting plasma glucose <140 mg/dl and 2-h postprandial plasma glucose <200 mg/dl. LDL particle size was evaluated by using high-resolution polyacrylamide gel electrophoresis (Lipoprint LDL™ System) and expressed by Rf value. LDL was incubated with 0.25 μM CuSO 4 for 20 h, and the degree of LDL oxidation was determined by malondialdehide analysis. Twenty-four-hour urinary C-peptide excretion and plasma triglyceride concentration in patients with microalbuminuria were significantly higher than those in normoalbuminuric patients. Rf values in microalbuminuric patients were significantly greater than those in normoalbuminuric patients. There were significantly inverse correlations between Rf value and α-tocopherol content in LDL, and between Rf value and LDL-free cholesterol/LDL-total cholesterol. Thiobarbituarte-reactive substance level in LDL had a tendency to correlate with Rf value and significantly inverse correlation to α-tocopherol content in LDL. In type 2 diabetics without hypertension, hypercholesterolemia and obvious obesity, smaller LDL particle size, accompanied by mild hyperinsulinemia and mild hypertriglyceridemia seems to be one of the important factors responsible for microalbuminuria. In addition, the present study suggests that the decrease of α-tocopherol content in small LDL particle is associated with oxidative susceptibility to Cu 2+-induced oxidation.

α-tocopherol is important to inhibit low-density lipoprotein oxidation in smokers

Smoking is recognized as an independent risk factor for atherosclerosis. This study was designed to study the effect of smoking on plasma and low-density lipoprotein (LDL) antioxidant concentrations and LDL oxidation susceptibility. A total of 89 subjects, consisting of 27 smokers and 62 nonsmokers, were recruited. Biochemical values and plasma ascorbic acid, α-tocopherol, and LDL α-tocopherol levels were assessed. LDL lag time, oxidation rate, and correlation between LDL α-tocopherol and LDL oxidation rate were determined. No differences were demonstrated for ascorbic acid and α-tocopherol concentrations in plasma between smokers and nonsmokers; however, LDL α-tocopherol was significantly higher for nonsmokers ( P = 0.012). Furthermore, the lag time for LDL oxidation was significantly longer for nonsmokers ( P = 0.019), whereas the LDL oxidation rate was significantly greater for smokers ( P = 0.018). Additionally, a highly significant negative correlation was demonstrated for LDL α-tocopherol concentration and LDL oxidation rate in smokers ( r = −0.440, P = 0.026), but not in nonsmokers. The results of this study suggest that LDL α-tocopherol is more susceptible to oxidative stress caused by smoking than ascorbic acid and α-tocopherol in plasma. For smokers, the presence of α-tocopherol in LDL effectively protects LDL from oxidation.

Dose-Response Study of Daily Cocoa Intake on the Oxidative Susceptibility of Low-Density Lipoprotein in Healthy Human Volunteers

A four-period crossover study was conducted to evaluate the dose-related response of daily cocoa intake on the oxidative susceptibility of low-density lipoprotein (LDL) in healthy human volunteers. Each supplementation phase consisted of a 14-day feeding period followed by a 28-day washout period. During the period, healthy male volunteers (n = 8) ingested 18, 24 or 36 g of cocoa powder per day (1.3, 1.74 or 2.61 g of polyphenols per day). During the control period, these subjects ingested sugar. LDL oxidative susceptibility was measured as the lag time of conjugated diene formation that started with the addition of a radical initiator, 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile). Samples were analyzed at pre-, one week, and two weeks post-supplementation. In the 24 and 36 g cocoa powder ingestion period, significant lag time prolongation was observed. We conclude that the ingestion of more than 24 g of cocoa powder per day (1.74 g of polyphenols) clearly protects LDL from oxidation.

Seasonal Variation in Copper-mediated Low-density Lipoprotein Oxidation In Vitro is Related to Varying Plasma Concentration of Oxidised Lipids in Summer and Winter

The seasonal variation of CuCl 2 -mediated low density lipoprotein (LDL) oxidation (10 w M Cu 2+ , lag phase, rate of oxidation and maximum absorbance at 234 nm) were measured in 43 men and women on 4-6 occasions (mean 5.7 - 0.5 ) over a 12-month period. The lag phase averaged 52.7 - 0.6 min and did not differ by gender. Lag phase and rate of the rapid propagation phase of LDL oxidation showed a sinusoidal pattern over the year (increased and reduced oxidative susceptibility during January and June-July, respectively; both p <0.001 ). Changes in plasma f -tocopherol, ascorbic acid, lycopene or g -carotene concentrations did not explain seasonal differences in oxidative susceptibility of LDL in vitro. Nor did plasma lipid content of linoleic acid, the main substrate of lipid peroxidation, vary. However, the amount of hydroperoxy- plus hydroxy-fatty acids in plasma lipids varied according to season ( p <0.024) and was related to the lag phase ( r = m 0.26, p <0.001). Seasonal variation in oxidative susceptibility was not significant after adjusting for hydroperoxy- plus hydroxy-fatty acids ( p =0.506). Isolated LDL is more vulnerable to Cu 2+ -induced lipid peroxidation during the winter and this may be due to the higher amount of oxidised lipids during that period.

Cocoa Products Decrease Low Density Lipoprotein Oxidative Susceptibility but Do Not Affect Biomarkers of Inflammation in Humans

Flavonoids and related polyphenolics with antioxidant and anti-inflammatory activities may play a role in the prevention of cardiovascular disease by decreasing oxidative stress and inflammation. We wished to determine the effects of cocoa extract supplementation on markers of oxidative stress and inflammation. Healthy subjects (n = 25) were studied at baseline, after cocoa supplementation (36.9 g of dark chocolate bar and 30.95 g of cocoa powder drink) for 6 wk and after a 6-wk washout period. Fasting blood and early morning urine were collected at the three time points. Two indices of flavonoid intake, total phenols and oxygen radical absorbance capacity of plasma, were measured after an overnight fast. Neither was affected by supplementation. Measures of oxidative stress included copper-catalyzed LDL oxidation kinetics and urinary F(2) isoprostanes. LDL oxidizability was lower after chocolate supplementation as evidenced by a longer lag time (P < 0.05) of conjugated diene formation (101.0 +/- 20.7 min) compared with baseline (91.3 +/- 18.0 min) and washout (96.4 +/- 7.5 min) phases. There was no effect of chocolate on urinary F(2) isoprostane levels or on markers of inflammation including the whole-blood cytokines, interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha, high sensitivity C-reactive protein and P-selectin. In conclusion, cocoa products supplementation in humans affects LDL oxidizability, but not urinary F(2) isoprostanes or markers of inflammation.

Decreased aortic early atherosclerosis in hypercholesterolemic hamsters fed oleic acid-rich TriSun oil compared to linoleic acid-rich sunflower oil

Previous studies have demonstrated that low density lipoprotein (LDL) enriched in polyunsaturated fatty acids (PUFA) are more susceptible to oxidation (ex vivo) than those containing monounsaturated fatty acids (MUFA). To test whether this observation was associated with various parameters considered to be related with the development of early aortic atherosclerosis, hamsters were fed commercial hypercholesterolemic diets (HCD) containing either the PUFA, sunflower oil (SF) or the MUFA, TriSun oil (TS) at 10% with 0.4% cholesterol (wt/wt). LDL isolated from hamsters fed TS had significantly longer lag phase (30%, P < 0.05), a decreased propagation phase (−62%, P < 0.005), and fewer conjugated dienes formed (−37%, P < 0.007) compared to hamsters fed SF. Aortic vasomotor function, measured as degree of aortic relaxation, was significantly greater in the TS vs SF-fed hamsters whether acetylcholine or the calcium ionophore A23187 was used as the endothelium-dependent agonist. As a group, the SF-fed hamsters had significantly more early atherosclerosis than hamsters fed TS (46%, P < 0.006). When animals across the two diets were pair-matched by plasma LDL-C levels, there was an 82% greater mean difference ( P < 0.002) in early atherosclerosis in the SF versus the TS-fed hamsters. While there were no significant associations with plasma lipids and lipoprotein cholesterol, early atherosclerosis was significantly correlated with lag phase (r = −0.67, p < 0.02), rate of LDL conjugated diene formation (r = 0.74, p < 0.006) and maximum dienes formed (r = 0.67, p < 0.02). Compared to TS-fed animals, aortic sections from hamsters fed the SF-containing diet revealed that the cytoplasm of numerous foam cells in the subendothelial space reacted positively with the monoclonal anti-bodies MDA-2 and NA59 antibody, epitopes found on oxidized forms of LDL. The present study suggests that compared to TS, hamsters fed the SF-diet demonstrated enhanced LDL oxidative susceptibility, reduced aortic relaxation, greater early aortic atherosclerosis and accumulation of epitopes found on oxidized forms of LDL.

Long chain polyunsaturated fatty acids may account for higher low-density lipoprotein oxidation susceptibility in Lithuanian compared to Swedish men

Objectives: Mortality in coronary heart disease among middle-aged men is four times higher in Lithuania than in Sweden. Traditional risk factors cannot account for this difference. We earlier reported that low-density lipoprotein (LDL) in Lithuanian men showed a lower resistance to oxidation, measured as LDL lag time during copper oxidation, than that in Swedish men. Serum concentrations of several fat-soluble antioxidant vitamins were lower among Lithuanian men. The aim of this study was to investigate whether differences in LDL fatty acid composition could account for the difference in LDL oxidation susceptibility between men in the two countries. Methods: This cross-sectional study included randomly selected healthy 50-year-old men from Vilnius, Lithuania (n = 50) and Linköping, Sweden (n = 50). Main outcome measures were fatty acids in LDL, phospholipid (PL) and cholesterol ester (CE) fractions of LDL and LDL oxidation susceptibility. Results: The mean proportions of PL 20:5n3 (eicosapentaenoic acid, EPA) were higher in Vilnius men (2.09 - 1.05 vs. 1.53 - 0.58%, p = 0.004). LDL lag time was shorter in Vilnius men, mean - SD (75.4 - 13.6 vs. 89.5 - 13.1 mins, p < 0.0001) than in Linköping men. Mean serum n -tocopherol was lower in Vilnius men (0.07 - 0.05 vs. 0.12 - 0.04 w g/mmol, p < 0.0001) but f -tocopherol did not differ. In a multiple regression analysis controlled for city, high PL-EPA, low alpha-tocopherol, and high plasma triglycerides significantly contributed to a short LDL lag time, r 2 = 0.53. Conclusions: Fat quality, i.e. poly unsaturated fatty acids, especially LDL-EPA, plasma triglycerides and antioxidative vitamins may partly account for the increased LDL oxidation susceptibility found in Vilnius men compared with Linköping men.

Increased DNA oxidative susceptibility without increased plasma LDL oxidizability in Type II diabetes: effects of α-tocopherol supplementation

In vivo supplementation studies of the antioxidant alpha-tocopherol in human Type II diabetes have used surrogate, rather than direct, markers of oxidative damage/antioxidant protection and have used higher doses of alpha-tocopherol than used in coronary secondary prevention trials. We tested the hypothesis that oral alpha-tocopherol in a dosage regimen used in secondary prevention trials would reduce directly observed oxidatively induced single-strand breaks in lymphocyte DNA in Type II diabetes. We studied 40 people with Type II diabetes and 30 controls in a randomized, double-blind, placebo-controlled trial of 400 i.u. of oral alpha-tocopherol daily for 8 weeks. Lymphocyte DNA single-strand breaks and low-density lipoprotein (LDL) particle size and oxidizability were measured at baseline, after 8 weeks, and after 4 weeks washout. Polymorphisms in the gene for the antioxidant enzyme paraoxonase-1 gene (position 192) were measured. The diabetics had increased DNA oxidative susceptibility (P=0.008), without increased LDL oxidative susceptibility. There was a direct relationship between DNA oxidative susceptibility and baseline plasma alpha-tocopherol in the diabetes group alone (r=0.421, r(2)=0.177 and P=0.023), but DNA and LDL oxidative susceptibility were not influenced by alpha-tocopherol supplementation in either group in this regimen. Paraoxonase-1 gene polymorphisms did not contribute to LDL or DNA oxidative susceptibility or response to alpha-tocopherol. Increased DNA oxidative susceptibility, therefore, can occur in Type II diabetes without increased LDL oxidative susceptibility, but alpha-tocopherol supplementation in this regimen has no influence on DNA or LDL oxidative susceptibility in Type II diabetes or controls. Polymorphisms in the paraoxonase gene (position 192) are not associated with differences in oxidative susceptibility or responses to alpha-tocopherol.

Low Fat and High Monounsaturated Fat Diets Decrease Human Low Density Lipoprotein Oxidative Susceptibility In Vitro

Oxidative modification of low density lipoprotein (LDL) is thought to play an important role in the development of atherosclerosis. Some studies have found that LDL enriched in monounsaturated fatty acids (MUFA) are less susceptible to oxidation than LDL enriched in polyunsaturated fatty acids (PUFA). A high MUFA diet is an alternative to a lower-fat blood cholesterol-lowering diet. Less is known about the effects of high MUFA versus lower-fat blood cholesterol-lowering diets on LDL oxidative susceptibility. The present study was designed to evaluate the effects of men and women consuming diets high in MUFA (peanuts plus peanut butter, peanut oil and olive oil) on LDL oxidative susceptibility, and to compare these effects with those of a Step II blood cholesterol-lowering diet. A randomized, double-blind, five-period crossover design (n = 20) was used to study the effects of the following diets on LDL-oxidation: average American [35% fat, 15% saturated fatty acids (SFA)], Step II (25% fat, 7% SFA), olive oil (35% fat, 7% SFA), peanut oil (35% fat, 7% SFA) and peanuts plus peanut butter (35% fat, 8% SFA). The average American diet resulted in the shortest lag time (57 +/- 6 min) for LDL oxidized ex vivo, whereas the Step II, olive oil and peanuts plus peanut butter diets resulted in a lag time of 66 +/- 6 min (P < or = 0.1). The slower rate of oxidation [nmol dienes/(min x mg LDL protein)] observed when subjects consumed the olive oil diet (24 +/- 2) versus the average American (28 +/- 2), peanut oil (28 +/- 2) and peanuts plus peanut butter diets (29 +/- 2; P < or = 0.05) was associated with a lower LDL PUFA content. The results of this study suggest that lower-fat and higher-fat blood cholesterol-lowering diets high in MUFA have similar effects on LDL oxidative resistance. In addition, our results suggest that different high MUFA sources varying in the ratio of MUFA to PUFA can be incorporated into a high MUFA diet without increasing the susceptibility of LDL to oxidation.

Evidence for inhibition of low density lipoprotein oxidation and cholesterol accumulation by apolipoprotein H (β 2-glycoprotein I)

Low density lipoprotein (LDL) oxidation and lipid accumulation are thought to enhance the progression of atherosclerosis. Apolipoprotein H (apoH) has been implicated in the development of human atherosclerosis. However, the roles of apoH in the oxidative modification of LDL and cellular accumulation of lipid constituents remained uncharacterized. In this study, the level of plasma apoH was found to be significantly associated with the oxidative susceptibility of LDL in human subjects. Plasma levels of apoH were positively correlated with the lag time but negatively correlated with LDL oxidation rate in conjugated diene formation. By using a J774 A.1 macrophage culture system, we found that apoH could not only inhibit the formation of conjugated diene and thiobarbituric acid-reactive substances, but also reduce the electrophoretic mobility of oxidized LDL. Furthermore, apoH decreased cellular accumulation of cholesterol via a reduction in cholesterol influx and an increase in cholesterol efflux. This is the first demonstration that apoH appears to have “antioxidant”-like effects on LDL oxidation. The results also suggest that apoH can inhibit the translocation of cholesterol from extracellular pools to macrophages, suggesting that apoH may play an important role in the prevention of atherosclerosis.