Effects of tomato juice consumption on plasma and lipoprotein carotenoid concentrations and the susceptibility of low density lipoprotein to oxidative modification.

Effects of tomato juice supplementation on the carotenoid concentration in lipoprotein fractions and the oxidative susceptibility of LDL were investigated in 31 healthy Japanese female students. These subjects were randomized to one of three treatment groups; Control, Low and High. The Control, Low and High groups consumed 480 g of a control drink, 160 g of tomato juice plus 320 g of the control drink, and 480 g of tomato juice, providing 0, 15 and 45 mg of lycopene, respectively, for one menstrual cycle. The ingestion of tomato juice, rich in lycopene but having little beta-carotene, increased both lycopene and beta-carotene. Sixty-nine percent of lycopene in plasma was distributed in the LDL fraction and 24% in the HDL fraction. In the Low group, the lycopene concentration increased 160% each in the VLDL+IDL, LDL and HDL fractions (p<0.01). In the High group, the lycopene concentration increased 270% each in the VLDL+IDL and LDL fractions, and 330% in the HDL fraction (p<0.01). Beta-carotene also increased 120% and 180% in LDL fractions of the Low and the High groups, respectively. Despite these carotenoid increases in LDL, the lag time before oxidation was not prolonged as compared with that of the Control group. The propagation rate decreased significantly after consumption in the High group. Multiple regression analysis showed a positive correlation between lag time changes and changes in the alpha-tocopherol concentration per triglyceride in LDL, and a negative correlation between propagation rate changes and changes in the lycopene concentration per phospholipid in LDL. These data suggest that alpha-tocopherol is a major determinant in protecting LDL from oxidation, while lycopene from tomato juice supplementaion may contribute to protect phospholipid in LDI, from oxidation. Thus, oral intake of lycopene might be beneficial for ameliorating atherosclerosis.

A case of aortic dissection with transient ST-segment elevation due to functional left main coronary artery obstruction.

A 48-year-old man with a history of hypertension and diabetes mellitus was hospitalized with sudden onset of severe chest pain. He was in cardiogenic shock with a systolic pressure of 60 mm Hg. His electrocardiogram (ECG) showed ST-segment elevation in the precordial leads suggestive of acute anteroseptal myocardial infarction. The ST-segment returned to baseline after the systolic blood pressure rose to 100 mm Hg with the administration of sympathomimetic agents. Aortography and transesophageal echocardiography demonstrated type A aortic dissection and aortic regurgitation. Aortography and short-axis transesophageal echocardiography showed during diastole almost complete collapse of the true lumen of the ascending aorta caused by the intimal flap. The patient underwent surgical repair of the aortic dissection and implantation of Palmaz stents in the carotid arteries. Decreased blood pressure and the presence of aortic regurgitation accelerated the collapse of the true lumen during diastole in the ascending aorta, resulting in functional obstruction of the left main coronary artery, which may have been related to ST-segment changes in this case.

Plasma levels and redox status of ascorbic acid and levels of lipid peroxidation products in active and passive smokers.

Both active and passive smoking are regarded as risk factors for various diseases. To clarify the effects of active and passive smoking on plasma vitamin C levels and lipid peroxidation status, we examined the plasma levels of ascorbic acid (AA), its redox status [ratio of dehydroascorbate (DHAA) to total AA], the levels of thiobarbiturate reactive substance (TBARS), and the levels of lipid peroxides (LPO) in smokers, nonsmokers, and nonsmokers regularly exposed to environmental cigarette smoke (passive smokers). The study population consisted of 149 healthy males: 75 active smokers (consumption of > 15 cigarettes/day for more than 5 years), 36 passive smokers (more than 10 hr/week exposure to environmental cigarette smoke), and 38 nonsmokers (no cigarette smoke exposure). There were no significant differences in plasma TBARS and LPO levels among the three groups. Plasma levels of AA, the reduced form of vitamin C, were significantly lower in active smokers than in the combined nonsmoking groups (7.2 +/- 3.5 and 8.4 +/- 3.4 microg/mL, respectively; p < 0.05). Although no significant differences were found in plasma DHAA levels among the three groups, the ratios of DHAA to total AA were significantly higher in active and passive smokers than nonexposed nonsmokers (11.2, 10.3, and 7.1%, respectively; p < 0.05). These results indicate that passive smoking, as well as direct inhalation of cigarette smoke, affects the redox status of plasma AA. In passive smokers, the altered redox status of plasma AA suggests an oxidative stress.

Effect of alcohol intake on the levels of plasma homocysteine in healthy males.

Hyperhomocysteinemia in chronic alcoholics has been reported, but it remains unclear whether relatively low alcohol intake compared with the previous reports affects the plasma homocysteine level. To investigate this issue, we performed two studies, a population-based study and an alcohol withdrawal study. An analysis of plasma homocysteine levels in a population of 236 healthy males showed no significant association between alcohol consumption and other tested parameters. In the withdrawal study, the subjects with a history of daily alcohol consumption (81.8 +/- 33.0 g/d, mean +/- SD, 40-150g/d, range) abstained from alcohol for 4 wk. After withdrawal, the levels of serum gamma-glutamyl transpeptidase, aspartate aminotransferase, triglycerides, and high-density lipoprotein cholesterol significantly decreased, but the plasma homocysteine level did not change. These results suggest that alcohol intake, at least as far as the amount of beverages our study subjects consumed, has no effect on the plasma homocysteine level in healthy males.

Endothelium-dependent flow-mediated vasodilation in the postprandial state in type 2 diabetes mellitus.

This study examined the effects of fat- plus sucrose-rich meals on endothelium-dependent flow-mediated vasodilation in diabetic patients. Flow-mediated vasodilation in the postprandial state decreased significantly, and the decrease correlated inversely with the magnitude of postprandial hyperglycemia, suggesting that endothelial function in diabetic patients becomes impaired postprandially.

Inhibitory effect of tea flavonoids on the ability of cells to oxidize low density lipoprotein.

Dietary flavonoid intake has been reported to be inversely related to mortality from coronary heart disease, and the anti-atherosclerotic effect of flavonoids is considered to be due probably to their antioxidant properties. Oxidation of low density lipoprotein (LDL) has been reported to be induced by the constituent cells of the arterial wall. Accordingly, we examined the effect of pretreatment with tea flavonoids, such as theaflavin digallate, on the ability of cells to oxidize LDL. Theaflavin digallate pretreatment of macrophages or endothelial cells reduced cell-mediated LDL oxidation in a concentration- (0-400 microM) and time- (0-4 hr) dependent manner. This inhibitory effect of flavonoids on cell-mediated LDL oxidation was in the order of theaflavin digallate > theaflavin > or = epigallocatechin gallate > epigallocatechin > gallic acid. Further, we investigated the mechanisms by which flavonoids inhibited cell-mediated LDL oxidation using macrophages and theaflavin digallate. Theaflavin digallate pretreatment decreased superoxide production of macrophages and chelated iron ions significantly. These results suggest that tea flavonoids attenuate the ability of the cell to oxidize LDL, probably by reducing superoxide production in cells and chelating iron ions.

Beneficial effect of gemfibrozil on the chemical composition and oxidative susceptibility of low density lipoprotein: a randomized, double-blind, placebo-controlled study.

Previous reports have shown that administration of fibrates can reduce coronary events and also improve plasma lipid levels. Oxidative modification of low density lipoprotein has been implicated in the pathogenesis of atherosclerosis, and the resistance of low density lipoprotein (LDL) to in vitro oxidation has been found to be correlated with the extent of atherosclerosis. We performed a double-blind, placebo-controlled intervention trial to establish whether gemfibrozil could improve resistance of LDL to oxidation in patients with hyperlipidemia. Patients were randomly assigned to treatment with gemfibrozil (450 mg, twice a day, n = 10) or placebo (n = 9) for 8 weeks. Blood samples were obtained after an overnight (12 h) fast. Gemfibrozil administration significantly reduced total plasma cholesterol and triglyceride levels and changed the LDL from small, dense particles (pattern B, < or = 25.5 nm) to larger, more buoyant particles (pattern A, > 25.5 nm). Gemfibrozil significantly increased the lag time of LDL oxidation in vitro by 18.2% from 45.5 +/- 8.0 min at week 0 to 53.4 +/- 11.4 min at week 8, but did not change LDL vitamin E and beta-carotene concentrations. Surprisingly, gemfibrozil significantly decreased LDL lipid peroxides by -33.1% and increased the LDL vitamin E/lipid peroxide ratio by 67.6% from 1.3 +/- 0.5 at week 0 to 2.1 +/- 0.9 at week 8. These results demonstrate that gemfibrozil treatment can render LDL less susceptible to oxidative modification while reducing plasma cholesterol and triglyceride and improving LDL subclass pattern. This antioxidative effect of gemfibrozil on LDL may be one of the factors which could delay the progression of atherosclerosis.

Effects of soy protein isolate (SPI) and casein on the postprandial lipemia in normolipidemic men.

To elucidate the effects of soybean protein and casein on postprandial lipemia, oral fat load tests were performed before and 3 weeks after the administration of soy protein isolate (SPI) and casein supplement to normolipidemic men. Eleven normolipidemic male subjects on otherwise identical controlled diets were assigned to either a 20 g/d soy protein isolate (SPI) dietary supplement or a casein dietary supplement for three weeks in a crossover design. Fat load tests with 40 g/m2 of bovine milk fat were carried out before and after 3 weeks on the experimental dietary supplements. Fasting plasma concentrations of lipids and apolipoproteins were not significantly different from baseline levels before or after the administration of SPI or casein supplemented diets. Neither SPI nor casein supplement affected the fasting plasma concentrations of lipids and apolipoproteins. The areas under the incremental curve (AUIC) of triglyceride (TG) and remnant-like particles triglyceride (RLP-TG) after both experimental diets were not significantly different from those before the experimental diets. However, the AUIC of remnant-like particles cholesterol (RLP-C) showed a tendency (p = 0.07) to decrease after administration of the diet supplemented with SPI than before the diet. The AUIC of RLP-C was significantly (p < 0.05) lower after the diet supplemented with SPI than after administration of the diet supplemented with casein. These results suggest that 3 weeks of 20 g/d SPI dietary supplement favorably affects the postprandial remnant lipoprotein response as compared to the casein dietary supplement.

Effect of supplementation with vitamin E on LDL oxidizability and prevention of atherosclerosis.

Supplementation of LDL with vitamin E is thought to protect LDL from oxidative modification and prevent the development of atherosclerosis. Large epidemiological studies have revealed that vitamin E levels in plasma are inversely correlated to the incidence of coronary heart disease. Double-blind placebo-controlled trials have reported that supplementation with vitamin E decreases the incidence of coronary events in coronary heart disease (CHD) patients. However, it is not clear how high a dose of vitamin E is needed to prevent formation of atherosclerosis. In animal studies, a diet containing 0.125% vitamin E increased its levels in plasma two-fold and prevented formation of early atherosclerotic lesions in the thoracic aorta of hypercholesterolemic rabbits. Dose-response studies in humans have reported that 400 IU/day vitamin E increased its levels in plasma two-fold and prolonged the lag time before LDL oxidation. It has been reported that oxidizability of LDL was correlated to the atherosclerotic score of coronary angiography in CHD patients. About 400 IU/day vitamin E, which increases its levels two-fold and prolongs sufficiently the lag time before LDL oxidation, might be beneficial in decreasing the individual risk of CHD.

Vitamin E reduces cholesterol esterification and uptake of acetylated low density lipoprotein in macrophages.

The effects of vitamin E on cholesteryl ester (CE) metabolism in J774 cells were examined. Pretreatment of J774 cells with vitamin E at concentrations above 50 microM significantly decreased acetylated low density lipoprotein (LDL)-induced incorporation of [14C]oleate into CE in cells in a dose-dependent manner. This was partly due to vitamin E also significantly inhibiting the uptake of [3H]CE-labeled acetylated LDL by J774 cells. A trend existed toward suppression of acyl-CoA:cholesterol acyltransferase (ACAT) activity in the cell lysate at high vitamin E concentration, but there was no effect on hydrolysis of CE. These data indicate that vitamin E reduces the uptake of modified LDL and suppresses ACAT activity, resulting in less cholesterol esterification in macrophages: a novel mechanism underlying the antiatherogenic properties of vitamin E.

Beneficial effects of alcohol withdrawal on LDL particle size distribution and oxidative susceptibility in subjects with alcohol-induced hypertriglyceridemia.

LDL subclass pattern B, reported to have a higher prevalence in hypertriglyceridemics (HTGs), is considered to be associated with an increased risk for coronary artery disease, and the small dense LDL characteristic of this pattern is susceptible to oxidative modification. Alcohol is considered one of the most frequent causes of increases in plasma triglyceride (TG) levels. We investigated the effects of alcohol withdrawal on LDL subclass distribution and oxidizability in drinkers with different plasma TG levels. Thirty-seven male subjects with relatively heavy alcohol-consumption habits were divided into four groups; normotriglyceridemic (NTG)/withdrawal (n = 11), NTG/control (n = 8), hypertriglyceridemic (HTG)/withdrawal (n = 10), and HTG/control (n = 8). Both withdrawal groups abstained form alcohol for 4 weeks, while the control subjects maintained their usual intake of alcohol. Peak LDL particle diameter (PPD) was smaller in the combined HTG groups than in the combined NTG groups before abstinence, although PPD increased significantly (P < .01) from 25.5 to 26.1 nm in the HTG/withdrawal group. Before abstinence, lag times preceding LDL oxidation in the combined HTG groups were shorter than in the combined NTG groups; after withdrawal, lag time was prolonged significantly (P < .01) from 49.9 to 57.3 minutes in the HTG-withdrawal group. No significant changes in PPD and lag time were observed in the other three groups. Significant correlations (P < .05) were observed between the change (delta) in the lag time and delta TG and between delta lag time and delta PPD. We conclude that in alcohol-induced HTG subjects, alcohol withdrawal has beneficial effects on the LDL profile by shifting the particle size from smaller to larger and decreasing its susceptibility to oxidation.

Effect of tea flavonoid supplementation on the susceptibility of low-density lipoprotein to oxidative modification.

Dietary flavonoid intake has been reported to be inversely associated with the incidence of coronary artery disease. To clarify the possible role of tea flavonoids in the prevention of atherosclerosis, we investigated the effects of tea flavonoids on the susceptibility of low-density lipoprotein (LDL) to oxidative modification. In an in vitro study, catechins or theaflavins (25-400 mumol/L) were added to plasma and incubated for 3 h at 37 degrees C. Then, the LDL fraction was separated by ultracentrifugation. The oxidizability of LDL was estimated by measuring conjugated diene, thiobarbituric acid-reactive substances (TBARS), and lipid peroxides after cupric sulfate was added. TBARS and lipid peroxides in the supernates were also measured after incubation with macrophages. Catechins significantly (P < 0.01 by ANOVA) and dose-dependently prolonged the lag time before initiation of oxidation. Among the catechins, epigallocatechin gallate exerted the most marked effect, prolonging the oxidation lag time more than vitamin E at the same molar concentration. Theaflavins exerted stronger inhibitory effects than catechins. Macrophage-mediated LDL oxidation was also inhibited by adding these tea flavonoids to the plasma samples. In an in vivo study, 14 healthy volunteers consumed 750 mL black tea/d for 4 wk. After the subjects had consumed tea for 4 wk, the lag time before LDL oxidation was significantly (P < 0.01) prolonged from 54 to 62 min. This minor prolongation occurred despite much lower plasma flavonoids than were used in vitro. No significant change was observed in eight control volunteers. LDL exposed to tea flavonoids in vitro or in vivo reduced oxidizability. We speculate that tea flavonoids may have a role in ameliorating atherosclerosis.

Effects of beta-blockers on HMG CoA reductase and LDL receptor activity in cultured human skin fibroblasts.

Previous reports, based on clinical trials and animal experiments, suggest that beta-blockers may be useful in the prevention of atherosclerosis. Betaxolol, a new beta1-selective blocker, was shown to decrease plasma total and LDL cholesterol levels or to have no adverse effect on those [1-4]. While many reports deal with metabolism of triglyceride and high density lipoprotein, fewer publications about cholesterol metabolism are currently available. To clarify the mechanism by which beta-blockers affect lipid metabolism, we examined the effects of beta-blockers on HMG CoA reductase and LDL receptor activity in cultured human skin fibroblasts. L-propranolol, a nonselective beta-blocker, increased HMG CoA reductase activity and decreased LDL receptor activity. However, d-propranolol had no major effects on HMG CoA reductase activity. These results suggest that beta-blockers act on HMG CoA reductase through the beta receptors. Beta1-blocking action should decrease HMG CoA reductase activity and increase LDL receptor activity. In fact, betaxolol, a beta1-selective blocker, decreased HMG CoA reductase activity and increased LDL receptor activity, but metoprolol had no major effect. We speculate that the discrepancy between betaxolol and metoprolol in the effect on HMG CoA reductase and the LDL receptor might be due to the difference of the extent of beta1-selectivity. We conclude that beta1-selective blockers are antihypertensive agents potentially valuable in the prevention of atherosclerosis.

Effect of low-dose simvastatin on cholesterol levels, oxidative susceptibility, and antioxidant levels of low-density lipoproteins in patients with hypercholesterolemia: a pilot study.

In this pilot study, 12 patients (6 men, 6 postmenopausal women) with hypercholesterolemia were treated with low-dose (5 mg/d) simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 4 weeks. Low-density lipoprotein (LDL) samples were isolated at the beginning (week 0) and at the end (week 4) of the treatment regimen. Simvastatin caused significant decreases of total cholesterol (-18.1%), LDL cholesterol (-27.6%), and apolipoprotein B (-21.8%), and significantly reduced total cholesterol, free cholesterol, cholesterol esters, phospholipids, and protein in LDL without significantly changing the component ratios and fatty acid levels of LDL. However, simvastatin therapy had no major effects on either antioxidant levels in LDL or the oxidative susceptibility of LDL. We conclude that low-dose simvastatin significantly reduces LDL cholesterol levels without increasing the oxidative susceptibility of LDL or decreasing the antioxidant levels of LDL, and thus may reduce the risk of coronary artery disease.

Effects of Ca-antagonists on oxidative susceptibility of low density lipoprotein (LDL).

Twelve adults (age 32-61 years) with essential hypertension were recruited from the outpatient clinics of National Defense Medical College hospital to serve as subjects in the present study. They were treated with nilvadipine, a Ca-antagonist, 4 mg b.i.d. for 4 weeks. LDL samples were isolated by ultracentrifugation at the beginning (week 0) and at the end (week 4) of the treatment regimen. The formation of conjugated dienes was measured by incubating 100 micrograms of LDL protein with 2 mumol CuSO4 in 2 ml phosphate buffered saline (PBS). There were no significant differences between lipids levels, composition and anti-oxidant levels of LDL at weeks 0 and 4. The lag time of LDL oxidation was 71.1 +/- 11.3 min at week 0 and 81.3 +/- 13.2 min at week 4 (p < 0.05). In vitro studies of LDL oxidation, evaluated by thiobarbituric acid reactive substances (TBARS) and by agarose electrophoretic mobility, indicated that nilvadipine inhibited the oxidative modification of LDL while amlodipine, used as control, did not. Nilvadipine, a lipophilic Ca-antagonist, significantly prolonged the lag time of conjugated diene formation of LDL by 12.6% but amlodipine, a hydrophilic Ca-antagonist, had no major effect on LDL oxidation. These results suggest that Ca-antagonists are effective for the prevention of atherosclerosis but the effect is dependent upon the lipophilicity of the drugs.

[Progress in the treatment of atherosclerotic vascular diseases].

The treatment of atherosclerotic vascular diseases has improved greatly. Clinical and epidemiological studies have recently revealed the following data. Changes in lifestyles is extremely effective and should be prevailed widely. Amelioration of atherosclerosis by drugs, including hypolipidemics, antihypertensives and antioxidant agents, is also confirmed. Skills and devices are much improved in PTCA and DCA which face the possibility of restenosis. Control of risk factors is also considered to be important to prevent restenosis.