Atsushi Yonemura

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.

Green Tea Consumption and Serum Malondialdehyde-Modified LDL Concentrations in Healthy Subjects

Objective: Green tea was shown to inhibit LDL oxidation, platelet aggregation, and matrix metalloproteinases (MMPs) activities in vitro. We tried to elucidate whether or not green tea consumption may have these effects in vivo, which may be protective against atherosclerotic disease. Methods: We measured serum malondialdehyde-modified LDL (MDA-LDL) concentrations and urine 8-epi-prostaglandin (PG) F2α in 22 healthy male nonsmokers. They drank 7 cups/day of water for 2 weeks and drank 7 cups/day of green tea for the next 2 weeks. Regarding platelet aggregation, plasma thromboxane B2 (TXB2) and 6-keto-PGF1α concentrations and ex vivo platelet aggregation were evaluated. Plasma MMP-2 and -9 concentrations were also measured. Results: Of the 22 subjects, 20 had been in the habit of drinking green tea before the study. Plasma catechins concentrations significantly decreased at the end of the water period and then increased at the end of the green tea period. Although no change in plasma LDL-cholesterol concentrations (110 ± 33 vs. 113 ± 28 mg/dL, p = NS) was found, MDA-LDL concentrations (84 ± 45 vs. 76 ± 40 IU/L, p < 0.05) and the ratio of MDA-LDL/LDL-cholesterol (0.74 ± 0.21 vs. 0.65 ± 0.20, p < 0.02) significantly decreased at the end of the green tea period. However, no significant changes were observed in urine 8-epi-PGF2α concentrations, in platelet aggregation, nor in plasma TXB2, 6-keto-PGF1α or MMP concentrations. Conclusion: Daily consumption of green tea decreased serum MDA-LDL concentrations, but it had no significant effects on platelet aggregation, platelet TX production or plasma MMPs concentrations. Our results suggest that green tea consumption may inhibit LDL oxidation in vivo.

Glucocorticoid Receptor Regulates ATP-Binding Cassette Transporter-A1 Expression and Apolipoprotein-Mediated Cholesterol Efflux from Macrophages

Objective—The ATP-binding cassette transporter-A1 (ABCA1) regulates cholesterol efflux from cells and is involved in high-density lipoprotein metabolism and atherogenesis. The objective of this study was to investigate the effect of dexamethasone (Dex) and other glucocorticoid receptor (GR) ligands on apolipoprotein AI–mediated cholesterol efflux from macrophages and ABCA1 expression in them. Methods and Results—Dex, a GR agonist, decreased ABCA1 mRNA levels in a dose- and time-dependent fashion, and RU486, a GR antagonist, reversed the inhibitory effect of Dex. The effects of Dex and RU486 on ABCA1 protein levels and apolipoprotein AI–mediated cholesterol efflux from the macrophages were consistent with these changes in mRNA levels. Transfected RAW264.7, together with a human ABCA1 promoter–luciferase construct, inhibited transcriptional activity by Dex and overexpression of human GR. Transrepression by GR was not mediated by liver X receptor (LXR), because there were no differences in the effects of the GR ligands on promoter activity between a reporter construct with mutations at the LXR binding site and one without the mutations, and no changes were brought about in ABCG1 and ABCG4 expression by GR ligands. Conclusions—Our results showed that GR ligands affected ABCA1 expression and cholesterol efflux from macrophages, which are regulated by GR through a LXR-independent mechanism.

Olive oil increases the magnitude of postprandial chylomicron remnants compared to milk fat and safflower oil.

OBJECTIVE The acute effects of olive oil, milk fat and safflower oil on postprandial lipemia and remnant lipoprotein metabolism were investigated. METHODS Eight Healthy male volunteers randomly underwent three types of oral fat-vitamin A loading tests. The test drink was a mixture of retinyl palmitate (RP)(50,000 IU of aqueous vitamin A/m2 body surface area) and one of the three types of oils (40 g of fat/m2 body surface area): olive oil (70.7% oleic acid of total fatty acids); milk fat (69.3% saturated fatty acid); safflower oil (74.2% linoleic acid). RESULTS Olive oil significantly increased plasma triacylglycerol and RP concentrations 4 hours after fat loading, as compared to other fats. Increases of remnant like particle concentrations were higher after olive oil than after the other two fats. CONCLUSION These results show that olive oil increases the magnitude of postprandial chylomicrons and chylomicron remnants compared to milk fat and safflower oil.

Effect of lipid-lowering therapy with atorvastatin on atherosclerotic aortic plaques: a 2-year follow-up by noninvasive MRI

Background Using MRI, we reported plaque regression in thoracic aorta and retardation of plaque progression in abdominal aorta by 1-year atorvastatin. However, association between serial plaque changes and LDL-cholesterol levels was not fully elucidated. Design A prospective, randomized, open-label trial. Methods We investigated the long-term effect of 20 versus 5-mg atorvastatin on thoracic and abdominal plaques and the association between plaque progression and on-treatment LDL-cholesterol levels in 36 hypercholesterolemia patients. MRI was performed at baseline and 1 and 2 years of treatment. Vessel wall area change was evaluated. Results The 20-mg dose markedly reduced LDL-cholesterol levels (−47%) versus 5-mg (−35%) dose. After 2 years of treatment, regression of thoracic plaques was found in the 20-mg group (−15% vessel wall area reduction), but not in the 5-mg group (+7%). Although the 20-mg dose induced plaque regression (−14%) from baseline to 1 year, no further regression was seen from 1 to 2 years of treatment (−1%). Regarding abdominal plaques, progression was found in the 5-mg group (+10%), but not in the 20-mg group (+2%). Plaque progression in the 5-mg group was found from baseline to 1 year (+8%), but not from 1 to 2 years (+2%). The degree of thoracic plaque regression correlated with LDL-cholesterol reduction (r = 0.61), whereas thoracic plaque change from 1 to 2 years correlated with on-treatment LDL-cholesterol levels (r = 0.64). Conclusion Twenty milligrams of atorvastatin regressed thoracic plaques. However, maintaining low LDL-cholesterol levels was needed to prevent plaque progression. In abdominal aorta, only retardation of plaque progression was found after 2 years of 20-mg treatment. Eur J Cardiovasc Prev Rehabil 16:222-228

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 anastrozole and tamoxifen on lipid metabolism in Japanese postmenopausal women with early breast cancer.

Endocrine therapies that profoundly decrease estrogen levels potentially have a detrimental effect on the cardiovascular system. This study evaluated the effect on lipid metabolism of one such agent, the new generation aromatase inhibitor anastrozole, compared with tamoxifen, when used as adjuvant treatment in postmenopausal Japanese women with early breast cancer. All patients had completed primary surgery and were randomized to anastrozole 1 mg once daily (n=22) or tamoxifen 20 mg once daily (n=22). Anastrozole significantly reduced levels of triglycerides and remnant-like particle cholesterol, whereas tamoxifen significantly increased these. Activity of lipoprotein lipase and levels of high-density lipoprotein cholesterol significantly increased after anastrozole treatment. In contrast, activity of hepatic triglyceride lipase, also a key enzyme of triglyceride metabolism, significantly decreased following treatment with tamoxifen. We thus conclude that in our study anastrozole had a beneficial effect on lipid profiles of postmenopausal women with early breast cancer after 12 weeks of treatment.

Effect of Atorvastatin on Plasma Osteopontin Levels in Patients With Hypercholesterolemia

To the Editor High levels of osteopontin (OPN) mRNA and proteins were reported in atherosclerotic plaques.1,2 OPN-transgenic mice developed marked atherosclerosis.3 We reported plasma OPN levels to be high in patients with coronary artery disease (CAD) and to correlate with the severity of CAD.4 We also reported high plasma levels of OPN in patients with restenosis.5 These suggest that OPN plays a role in the development of atherosclerosis. In vitro, Takemoto et al6 demonstrated statins to reduce OPN mRNA in cultured aortic smooth muscle cells and upregulated OPN mRNA in aorta of diabetic rats. We investigated the effects of 20 mg/d versus 5 mg/d atorvastatin on plasma OPN levels in 40 hypercholesterolemic patients without any history of cardiovascular disease. Our study was approved by institutional ethics committee. If patients were taking statins, these were discontinued. After 4-week washout period, fasting blood samples were taken after informed consent was obtained. If LDL-cholesterol >150 mg/dL, patients …

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 1774 cells were examined. Pretreatment of 1774 cells with vitamin E at concentrations above 50 μM significantly decreased acetylated low density lipoprotein (LDL)-induced incorporation of [14C]oleate into CF 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 1774 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.

Increasing physical fitness does not proportionally decrease circulating C-reactive protein level in men with varying fitness

Several studies have shown that low physical fitness is associated with high levels of C-reactive protein (CRP), a marker of future cardiovascular events. However, whether increasing physical fitness proportionally decreases the circulating CRP level has not been evaluated. We first evaluated the basic relationship between physical fitness, assessed by running velocity, and circulating CRP level along with cardiovascular risk factors in 1065 healthy middle-aged men. Afterward, we examined the association between annual change in fitness and changes in CRP level in 482 subjects who had the same parameters measured 1 year later without any intervention. In the cross-sectional study, physical fitness was significantly correlated with circulating CRP level (r=0.28, P<.0001). This significance still remained after adjustment for other cardiovascular risks (beta=-.12, P=.0004). In the follow-up study, several variables, including CRP, were significantly improved (CRP geometric mean, from 0.35 to 0.26 mg/L; P<.001). Improvements in fitness did not reach statistical difference (P=.067). Annual change in CRP was significantly correlated with creatinine kinase level 1 year later (r=0.16, P=.004) and with annual changes in some other risks, but not with annual change in fitness. When follow-up subjects were divided into tertiles according to increase in fitness, the greatest reduction in CRP was found in subjects with mildly increased fitness and favorable risk profiles (n=159; CRP geometric mean, from 0.35 to 0.21 mg/L; P<.0001), but not in those with moderately to highly increased fitness (n=113; geometric mean, from 0.36 to 0.28 mg/L; P=.03). In conclusion, although physical fitness was significantly associated with circulating CRP level in a cross-sectional study, increasing fitness did not proportionally decrease circulating CRP level. Improving coincidental risks, relieving intensity of exercise-induced muscle damage, or both, in addition to increasing fitness, might be important to effectively reduce CRP level.