Hiroshi Hosoai

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.

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

SummaryPrevious 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 the 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 betablocker, 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.

Efficacy and Effects on Lipid Metabolism of Combination Treatment With Losartan + Hydrochlorothiazide Versus Losartan + Amlodipine: A 48-Week Prospective, Multicenter, Randomized, Open-Label Trial

BACKGROUND Both combination therapies of an angiotensin II receptor blocker (ARB) with the thiazide diuretic hydrochlorothiazide (HCTZ) and an ARB with a calcium channel blocker (CCB) are recommended to achieve blood pressure (BP) goals in antihypertensive treatment. However, although HCTZ is known to have unfavorable effects on lipid metabolism, the effects of HCTZ in the ARB + HCTZ combination on lipid metabolism have not been fully elucidated. OBJECTIVE The aim of this study was to compare the effects on lipid metabolism of combination treatment with the ARB losartan + HCTZ and losartan + the CCB amlodipine and to assess the efficacy in BP lowering of these 2 combination therapies. The metabolism of glucose, uric acid (UA), and high-sensitivity C-reactive protein (hs-CRP), an inflammation marker of atherosclerosis, were also assessed in association with lipid metabolism. METHODS This 48-week, prospective, randomized, open-label trial was conducted at 2 clinics and 2 hospitals in Tokorozawa City (Saitama, Japan) and Shinjuku-ku Ward (Tokyo, Japan). Eligible patients had a systolic BP (SBP) >140 mm Hg and/or diastolic BP (DBP) >90 mm Hg despite a >1-month history of monotherapy with an ARB. Patients were randomly assigned to receive losartan 50 mg/d + HCTZ 12.5 mg/d (LOS + HCTZ) or losartan 50 mg/d + amlodipine 5 mg/d (LOS + CCB) for 48 weeks. Follow-up visits were scheduled at 4, 8, 12, 24, and 48 weeks. Biochemical measurements were centrally measured at a single institute. Tolerability and treatment compliance were assessed by physicians every 4 weeks. RESULTS A total of 112 patients were enrolled; 26 were excluded from the final analysis, leaving 42 and 44 patients in the LOS + HCTZ and LOS + CCB groups, respectively, included in the final analysis. At 48 weeks, SBP and DBP were significantly decreased in the 2 treatment groups (both, P < 0.0001). The decrease in SBP was significantly greater in the LOS + HCTZ group than in the LOS + CCB group (P < 0.001). The difference in the decrease in DBP between the 2 groups was nonsignificant. There were no significant differences in the changes from baseline (Δ) in any of the lipid parameters between the 2 groups. The decreases at 8 and 12 weeks in LDL-C, TC, and apolipoprotein (apo) B were significantly greater in the LOS + CCB group compared with those in the LOS + HCTZ group. The between-group differences in ΔTG, ΔHDL-C, ΔapoA-1, and ΔapoE throughout the study were nonsignificant. Changes in fasting plasma glucose (FPG), hemoglobin A1c, and hs-CRP were not significantly different between the 2 groups. The between-group difference in ΔUA in men was not significant, but a significant difference was found in women (LOS + HCTZ, 0.74 mg/dL; LOS + CCB, 0.28 mg/dL [P = 0.0017]). No clinically significant adverse events were reported with either treatment throughout the study. CONCLUSIONS The findings from the present study suggest that LOS + HCTZ was more efficacious in decreasing SBP than was LOS + CCB in the management of hypertension refractory to ARB monotherapy. Unfavorable effects on lipid metabolism were not observed with either combination therapy.