Yuji Yasunobu

Coronary atherosclerosis and oxidative stress as reflected by autoantibodies against oxidized low-density lipoprotein and oxysterols.

Clinical studies and animal experiments have demonstrated that oxidized low-density lipoprotein (oxLDL) and oxysterols play important roles in atherogenesis. OxLDL is immunogenic, and autoantibodies (Ab) against oxLDL are detectable in serum. We investigated the relevance of oxysterols and Ab against-oxLDL to coronary artery disease (CAD) in 183 patients undergoing coronary angiography. Patient groups included angiographically normal subjects (< 75% stenosis), others with spasm (> 75% narrowing in response to acetylcholine), and some others with fixed stenosis (> 75%). The group with stenosis was subdivided into patients with stable and unstable angina. Serum concentrations of autoantibodies and 25-, 27-, and 7-beta-hydroxycholesterols were significantly higher in the stenotic group than in the normal group (P < 0.01, P < 0.05, P < 0.05, and P < 0.05, respectively). Antibodies, but not oxysterol concentrations, were significantly greater in subjects with unstable than with stable angina (P < 0.01). We conclude that anti-oxLDL antibody and oxysterol concentrations are associated with coronary artery stenosis, and that oxidative stress may be greatly increased in unstable angina.

Opposite effects on cholesterol metabolism and their mechanisms induced by dietary oleic acid and palmitic acid in hamsters

The effects of dietary oleic acid on cholesterol metabolism were investigated and compared with those of palmitic acid in hamsters. Addition of 5% oleic acid to a 0.1% cholesterol-supplemented diet decreased plasma total cholesterol, very low density lipoprotein (VLDL) cholesterol, and low density lipoprotein (LDL) cholesterol, increased hepatic LDL receptor activity, and decreased plasma cholesteryl ester transfer protein (CETP) activity in comparison with 0.1% cholesterol alone. In contrast, addition of 5% palmitic acid to a 0.1% cholesterol-supplemented diet increased total cholesterol and LDL-cholesterol, increased plasma CETP activity, and suppressed hepatic LDL receptor activity to a greater extent than 0.1% cholesterol alone. Neither oleic acid nor palmitic acid altered hepatic microsomal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, but oleic acid increased hepatic microsomal cholesterol 7 alpha-hydroxylase activity. These results suggest that dietary oleic acid inhibits the increases in total, VLDL-, and LDL-cholesterol induced by dietary cholesterol by preventing both LDL receptor suppression and increased CETP activity, whereas dietary palmitic acid augments the cholesterol-induced increases in total and LDL-cholesterol by both further suppression of LDL receptor activity and further stimulation of CETP activity.

DECREASES IN PLASMA LIPID CONTENT AND THROMBOTIC ACTIVITY BY ETHYL ICOSAPENTATE PURIFIED FROM FISH OILS

Abstract The effects of ethyl icosapentate (purified from fish oils) on plasma lipids, activity of coagulation factors VII and X, and content of plasminogen activator inhibitor-1 were examined in 28 patients with familial combined hyperlipidemia. After 8 weeks, ethyl icosapentate at 1800 mg daily significantly decreased plasma total cholesterol and triglyceride levels, activity of coagulation factors VII and X, and content of plasminogen activator inhibitor-1 without deleterious effects on plasma low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and plasma apolipoproteins. Activity of coagulation factors VII and X and the content of plasminogen activator inhibitor-1 correlated with triglyceride levels at week 0 while only coagulation factor VII correlated with total cholesterol at week 0. Changes in coagulation factor activity and content of plasminogen activator inhibitor-1 did not correlate with that of plasma total cholesterol or triglyceride after 8 weeks. Purified ethyl icosapentate would thus appear to have an antiatherogenic effect and could be essential in the control of coronary heart disease by lowering plasma lipid content and increasing antithrombotic action.

Reduction of Plasma Cholesterol Levels and Induction of Hepatic LDL Receptor by Cerivastatin Sodium (CAS 143201-11-0, BAY w 6228), a New Inhibitor of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase, in Dogs

The effects of cerivastatin sodium (BAY w 6228), a new type of inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on plasma cholesterol concentrations and the induction of hepatic LDL receptors were investigated with beagle dogs and Hep G2 cells. Oral administration of cerivastatin (0.01, 0.03, and 0.1 mg/kg per day) for 3 weeks reduced plasma total and very low-density lipoprotein plus low-density lipoprotein (VLDL + LDL) cholesterol concentrations and increased hepatic LDL receptor binding activity in dogs. Scatchard plot analysis revealed a 1.9-fold increase in the maximum binding capacity of hepatic LDL receptors in cerivastatin-treated animals. Similar results were obtained by administration of pravastatin (1.0 and 5.0 mg/kg/day) for 3 weeks. Binding activity of the LDL receptor, as well as receptor mRNA and protein concentrations, were increased in a dose-dependent manner (0.01–1.0 μM) by exposure of Hep G2 cells to cerivastatin. The results suggest that cerivastatin reduces plasma cholesterol concentrations by increasing hepatic LDL receptor expression. The mechanism of lowering cholesterol concentration by cerivastatin was the same as with the other previously examined HMG-CoA reductase inhibitors, but the effects with cerivastatin were apparent at doses much lower than the effective doses of the other drugs. Cerivastatin, therefore, shows potential for clinical use as a potent and efficacious plasma cholesterol-lowering drug.

Comparison of the Effect of Bezafibrate on Improvement of Atherogenic Lipoproteins in Japanese Familial Combined Hyperlipidemic Patients With or Without Impaired Glucose Tolerance

The effect of bezafibrate on plasma lipoproteins was investigated in Japanese familial combined hyperlipidemic patients with or without an impaired glucose tolerance accompanied by a low-density lipoprotein subclass, with the major gradient gel peak at a particle diameter of less than 25.5 nm. Bezafibrate treatment at a dose of 400 mg/d for 12 weeks produced an antiatherogenic effect on lipoprotein profiles, as reflected by a decrease in plasma triglyceride levels, an increase in plasma high-density lipoprotein-cholesterol levels, induction of the large-size subclass of low-density lipoprotein, and disappearance of intermediate-density lipoproteins. The plasma total and low-density lipoprotein-cholesterol-lowering effect of bezafibrate was significant in patients without impaired glucose tolerance but was not significant in patients with impaired glucose tolerance. Bezafibrate increased lipoprotein lipase activity and decreased the activity of cholesteryl ester transfer protein, both in patients with or without impaired glucose tolerance. There was no difference in the distribution of signal peptide insertion/deletion or Xbal polymorphisms of the apolipoprotein B gene in patients with or without impaired glucose tolerance. Mechanisms other than lipoprotein lipase, cholesteryl ester transfer protein activities, and an apolipoprotein B gene polymorphism may be responsible for the resistance to lowering of plasma total and low-density lipoprotein cholesterol levels with bezafibrate treatment in familial combined hyperlipidemic patients with impaired glucose tolerance.

Effect of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on hepatic cholesterol 7α-hydroxylase, acyl-coenzyme A: cholesterol acyltransferase, and bile lipid secretion in the hamster with intact enterohepatic circulation

The effects of administration of pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on hepatic cholesterol 7 alpha-hydroxylase and acyl-coenzyme A: cholesterol acyltransferase (ACAT) activities and bile lipid secretion were investigated in Syrian golden hamsters. Continuous administration of pravastatin induced no significant changes in hepatic cholesterol content, ACAT and cholesterol 7 alpha-hydroxylase activities, or bile lipid and acid composition. Abrupt withdrawal of pravastatin induced increases in hepatic cholesterol content and ACAT activity and no change in hepatic cholesterol 7 alpha-hydroxylase activity, and increased cholesterol saturation in bile. Hepatic cholesterol 7 alpha-hydroxylase activity paralleled hepatic mRNA levels of this enzyme. These results suggest that a change in hepatic cholesterol metabolism induced by continuous administration of pravastatin maintains a constant net balance of hepatic cholesterol content. In addition, the drug has no deleterious influence on metabolism of bile lipids and acids and related enzymes, except for a transient increase in cholesterol saturation in bile induced by an inappropriate increase in hepatic cholesterol content and a lack of response of cholesterol 7 alpha-hydroxylase activity to changes in hepatic cholesterol content upon abrupt withdrawal of pravastatin.

Hypolipidemic effect of beraprost sodium in patients with arteriosclerosis obliterans accompanied by hyperlipidemia

Abstract The effect of beraprost sodium, a stable prostaglandin I 2 analog, on plasma lipids and apolipoproteins was examined in 18 patients with arteriosclerosis obliterans (Fontaine I) accompanied by hyperlipidemia. Twelve weeks of therapy with beraprost sodium at 120 μg daily significantly decreased plasma total cholesterol and low-density lipoprotein (LDL) cholesterol levels without a deleterious effect on plasma triglyceride, high-density lipoprotein (HDL) cholesterol, or apolipoprotein levels. A positive correlation was observed between the change in plasma total cholesterol and that in plasma LDL cholesterol due to the administration of beraprost sodium. Although this is a preliminary study, the results suggest beraprost sodium exerts an antiatherogenic effect. By lowering plasma total cholesterol and LDL cholesterol levels, beraprost sodium may prove to be important in the control of arteriosclerosis obliterans with hyperlipidemia.

Pentaerythritol tetranicotinate (niceritrol) decreases plasma lipoprotein(a) levels

We determined the most effective dosage of pentaerythritol tetranicotinate (niceritrol) to reduce plasma lipoprotein(a) [Lp(a)] levels in 44 Japanese patients (16 men and 28 women; mean age, 59.2 +/- 10.8 years) with hyperlipidemia types IIa, IIb, and IV. Patients received oral niceritrol at a dosage of 750 mg (3 tablets)/d for 8 weeks, followed by 1,500 mg (6 tablets)/d for 8 weeks. Administration of niceritrol 750 mg/d for 8 weeks decreased total and low-density lipoprotein (LDL) cholesterol in patients with type IIa hyperlipidemia and decreased triglycerides in patients with type IV hyperlipidemia, but did not affect Lp(a). However, niceritrol 1,500 mg/d for 8 weeks decreased Lp(a) in patients with initial Lp(a) levels greater than 30 mg/dL in addition to decreasing total and LDL cholesterol and triglycerides. These results suggest that the effective dosage of niceritrol to reduce the serum Lp(a) concentration in Japanese hyperlipidemic patients with a high Lp(a) level (> or = 30 mg/dL) is greater than 1,500 mg/d.

Hypolipidemic effect of saiko-ka-ryukotsu-borei-to (TJ-12) in patients with type II or type IV hyperlipidemia

Abstract This open-label, uncontrolled trial evaluated the effect of Kampo medicine. Saiko-ka-ryukotsu-borei-to (TJ-12), on plasma lipids and apolipoproteins in 21 patients (3 men and 18 women) with type II or type IV hyperlipidemia. The mean age of the patients was 60.2 ± 7.2 years and the mean weight was 55.9 ± 9.4 kg. Twelve weeks after daily administration of 7.5 g of TJ-12, total cholesterol levels, low-density lipoprotein (LDL)-cholesterol levels, and the atherogenic index (defined as the difference between total cholesterol levels and high-density lipoprotein [HDL]-cholesterol levels divided by HDL-cholesterol levels) were significantly decreased (pretreatment vs posttreatment mean value, 263 ± 31 mg/dL vs 239 ± 36 mg/dL, 177 ± 39 mg/dL vs 163 ± 35 mg/dL, and 4.3 ± 8.9 mg/dL vs 3.8 ± 8.7 mg/DL, respectively). There was a significant positive correlation between the change in total cholesterol levels and that in LDL-cholesterol levels. These results suggest that TJ-12 might diminish atherogenesis by reducing the plasma levels of total cholesterol and LDL-cholesterol.