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N Kume

Publications and source records attributed to N Kume.

139 records · Page 8Linked to original sources
PubMed1991

Receptors for modified low-density lipoproteins on human endothelial cells: different recognition for acetylated low-density lipoprotein and oxidized low-density lipoprotein.

We examined the uptake pathway of acetylated low-density lipoprotein and oxidatively modified LDL (oxidized LDL) in human umbilical vein endothelial cells in culture. Proteolytic degradation of 125I-labeled Ac-LDL or Ox-LDL in the confluent monolayer of human endothelial cells was time-dependent and showed saturation kinetics in the dose-response relationship, which suggests that their incorporation is receptor-mediated. Cross-competition studies between acetylated LDL and oxidized LDL showed that the degradation of 125I-labeled acetylated LDL was almost completely inhibited by excess amount of unlabeled acetylated LDL, while only partially inhibited by excess unlabeled oxidized LDL. On the other hand, the degradation of 125I-labeled oxidized LDL was equally inhibited by excess amount of either acetylated or oxidized LDL. Cross-competition results of the cell-association assay paralleled the results shown in the degradation assay. These data indicate that human endothelial cells do not have any additional receptors specific only for oxidized LDL. On the contrary, they may have additional receptors, as we previously indicated on mouse macrophages, which recognize acetylated LDL, but not oxidized LDL.

Binding, Competitive↗
PubMed1990

The role of oxidized low density lipoprotein in the pathogenesis of atherosclerosis.

Recently, it has been suggested that oxidized low density lipoprotein (LDL) plays an important role in atherogenesis by facilitating the accumulation of lipids in macrophages. In vitro studies from our laboratory have shown that oxidized LDL is recognized not only by a specific receptor, but also by a receptor which recognizes both oxidized LDL and acetyl LDL. Probucol, originally developed as an antioxidant, prevents the oxidative modification of LDL in vitro. Our recent studies show that probucol prevents the progression of atherosclerosis in homozygous WHHL rabbits in vivo without any changes in plasma LDL cholesterol levels. These results strongly suggest that oxidative modification of LDL could occur in vivo and probucol could slow the progression of atherosclerosis, especially the foam cell-rich fatty streak lesions, without changing plasma cholesterol levels.

Animals↗
PubMed1989

Induction of mRNA for low-density lipoprotein receptors in heterozygous Watanabe heritable hyperlipidemic rabbits treated with CS-514 (Pravastatin) and cholestyramine.

We administered CS-514, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, alone and in combination with cholestyramine to heterozygous Watanabe heritable hyperlipidemic rabbits. This rabbit model for heterozygous familial hypercholesterolemia has hepatic low-density lipoprotein receptors that are assumed to be half as many as in normal rabbits. CS-514 alone lowered plasma low-density lipoprotein cholesterol levels by 50%, and in combination with cholestyramine, it lowered levels by 80%. The membrane-binding assay showed these drugs caused 1.5- and 1.8-fold increases in the number of hepatic low-density lipoprotein receptors, respectively. We also measured the amount of mRNA for low-density lipoprotein receptor by S1 nuclease protection assay in the same livers as above. These drugs induced mutant mRNA for the low-density lipoprotein receptor, which has an in-flame deletion of 12 nucleotides, as well as normal receptor mRNA. CS-514 alone produced a 1.8-fold increase in the amount of mRNA for the normal receptor and a 2.3-fold increase for the mutant mRNA, whereas CS-514 in combination with cholestyramine produced 1.9- and 3.1-fold increases, respectively. We conclude that CS-514 induces mRNA for the low-density lipoprotein receptor, subsequently increasing the receptor protein in the liver, and then reduces the levels of plasma cholesterol, and that the induction is augmented when the drug is administered in combination with cholestyramine.

Animals↗
PubMed1989

Characterization of very low density lipoprotein from Watanabe heritable hyperlipidemic rabbits.

We investigated the properties of very low density lipoprotein (VLDL) from two types of Watanabe heritable hyperlipidemic (WHHL) rabbits: one with a high incidence of coronary atherosclerosis (type 1), and the other with a low incidence (type 2). When incubated with mouse peritoneal macrophages, VLDL from type 1 WHHL rabbit (type 1-VLDL) stimulated cholesteryl ester synthesis 10.5-fold more than VLDL from the type 2 WHHL rabbit (type 2-VLDL) did. Moreover, a similar difference was seen in the stimulation of cholesteryl ester synthesis in peritoneal macrophages isolated from the WHHL rabbits. The mass ratios of cholesterol to protein in type 1- and type 2-VLDL were 5.69 and 2.05, respectively. Agarose gel electrophoresis of type 1-VLDL showed beta mobility, and that of type 2-VLDL showed pre-beta mobility. No difference was seen between the sizes of VLDL particles of the two types. The amount of apolipoprotein E in type 1-VLDL was greater than that in type 2-VLDL. In conclusion, the difference between type 1 and type 2 WHHL rabbits is at least partly due to the presence in type 1 animals of VLDL particles rich in cholesteryl esters and apolipoprotein E, particles which are very similar to beta-VLDL in conformation.

Animals↗
PubMed1988

Uptake of acetylated LDL by peritoneal macrophages obtained from normal and Watanabe heritable hyperlipidemic rabbits, an animal model for familial hypercholesterolemia.

Acetylated low-density lipoprotein (acetyl-LDL) stimulated the incorporation of [14C]oleate into cholesteryl [14C]oleate in peritoneal macrophages from both normal and Watanabe heritable hyperlipidemic (WHHL) rabbits. A degradation study showed that macrophages from WHHL rabbits degraded the same amount of 125I-labeled acetyl-LDL as macrophages from normal rabbits. These findings indicate that macrophages of WHHL rabbits have functional acetyl-LDL receptors.

Animals↗
PubMed1988

Prevention of atherosclerotic progression in Watanabe rabbits by probucol.

The foam cell has been recognized as a characteristic feature of xanthomas in skin and tendons, and also of atheromas. Many foam cells in these lesions share properties characteristic of the macrophages. Therefore macrophages may be the progenitor of certain foam cells that are involved in atherogenesis. Several investigators demonstrated in vitro that macrophages can ingest large amounts of certain chemically modified lipoproteins, such as acetylated low-density lipoprotein (LDL) and malondialdehyde-treated LDL, through the process of receptor-mediated endocytosis. By this process, macrophages become foam cells. But this process has not been demonstrated in vivo. Recently, oxidized LDL has been suggested to play an important role in atherogenesis by facilitating the accumulation of lipids in macrophages in vitro. Probucol, originally developed as an antioxidant, prevents this oxidative modification of LDL in vitro. Moreover, there are some clinical reports that probucol induces regression of cutaneous and tendon xanthomas in patients with homozygous familial hypercholesterolemia. A question was posed whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At age 2 months, 8 WHHL rabbits were classified into 2 groups: group A rabbits were controls and group B rabbits were treated with 1% probucol. After 6 months of treatment, average plasma concentrations of cholesterol were 704 +/- 121 mg/dl in group A and 584 +/- 61 mg/dl in group B. The percentage of surface area of total thoracic aorta with visible plaques in group A vs group B was 54.2 +/- 18.8% vs 7.0 +/- 6.3%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The concentration of serum lipids in Zen monks and control males in Japan.

The concentrations of total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, triglyceride and apoprotein B have been examined in Zen monks whose intake of animal products was almost negligible for 2 to 8 years, and in age-matched (24 to 35 years) control Japanese males who eat Western style food. The mean levels of total, LDL- and HDL-cholesterol, and apoprotein B were 135.1 +/- 16.7, 73.0 +/- 11.6, 50.4 +/- 9.6, and 70.6 +/- 15.6 mg/dl, respectively in Zen monks. These levels were 28.5, 32.8, 18.8, and 23.9% lower in Zen monks than in control Japanese males. These values are statistically significant compared to those of the controls (p less than 0.01). There were no significant changes in the level of triglyceride in both groups.

Adult↗
PubMed1987

Clinical significance of early myocardial 99mTc-pyrophosphate uptake in patients with acute myocardial infarction.

Early 99mTc-pyrophosphate (PYP) scintigrams of 29 patients receiving coronary thrombolysis induced by urokinase, 3.9 +/- 1.2 hours after the onset of acute myocardial infarction (AMI), were evaluated. Intravenous 99mTc-PYP scintigraphy was performed 2.8 to 8.0 hours after the onset of AMI. All 19 patients with positive findings on early scintigrams had good recanalization, compared to only 3 of the 10 patients with negative findings. The seven patients with unsuccessful recanalization after coronary thrombolysis had total occlusion or subtotal occlusion with delayed washout of contrast material, and three of them had collaterals. The sensitivity, specificity, and predictive accuracy of positive results of early scintigraphy in predicting the presence of early reperfusion were 73%, 100%, and 90%, respectively. Patients with positive early scintigrams showed increasing regional ejection fraction and decreasing thallium defect scores from the acute stage to the chronic stage. These findings indicate that early 99mTc-PYP scintigraphy is a sensitive noninvasive technique for detecting early recanalization in infarcted vessels. The collateral flow or antegrade flow with delay is not enough to cause 99mTc-PYP uptake in a very early stage of AMI.

Aged↗
PubMed1987

Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia.

In this study, we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At 2 months of age, eight WHHL rabbits were divided into two groups. Group A (n = 4) was fed standard rabbit chow for 6 months. Group B (n = 4) was fed standard rabbit chow containing 1% probucol for 6 months. At the end of the experiments, average plasma concentrations of cholesterol were 704 +/- 121 mg/dl in group A and 584 +/- 61 mg/dl in group B, respectively. The percentage of surface area of total thoracic aorta with visible plaques in group A versus group B was 54.2% +/- 18.8% versus 7.0% +/- 6.3%, respectively. What was noteworthy was that the percentage of plaque in the descending thoracic aorta was almost negligible (0.2% +/- 0.2%) in group B rabbits compared to that in group A rabbits (41.1% +/- 20.2%). Low density lipoproteins (LDL) isolated from WHHL rabbits under treatment with probucol (group B) were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. On the contrary, LDL from group A rabbits incubated with cupric ion showed a 7.4-fold increase in peroxides (thiobarbituric acid-reactive substances) and a 4.3-fold increase in the synthesis of cholesteryl ester in macrophages compared to those of LDL from group B rabbits. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages.

Animals↗
PubMedDate not supplied

Probucol does not affect lipoprotein metabolism in macrophages of Watanabe heritable hyperlipidemic rabbits.

We recently reported that the antioxidant action of probucol inhibited the progression of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits. In this study, we investigated another possible action of probucol: its action as an antiatherogenic agent on macrophages. When WHHL rabbit peritoneal macrophages were pre-incubated in vitro with probucol and then incubated with several atherogenic lipoproteins, the incorporation of the lipoproteins was not significantly prevented. In the case of mouse peritoneal macrophages, pre-incubation with probucol showed slight, although not statistically significant, changes in the amount of lipoprotein incorporations. We also used macrophages obtained from mice and WHHL rabbits fed with probucol, but the amount of uptake of lipoproteins by these cells was not less than that by control macrophages. Furthermore, to investigate the incorporation of atherogenic lipoproteins into these cells, we prepared probucol-containing macrophages; however, probucol in macrophages failed to prevent the uptake of such lipoproteins. In conclusion, probucol did not prevent foam cell transformation of macrophages of WHHL rabbit or mice directly, and the effect of probucol against atherogenesis in WHHL rabbits was due mainly to its inhibitory effect on the oxidative modification of low density lipoprotein, as previously reported.

Animals↗