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M Yokode

Publications and source records attributed to M Yokode.

At least 55 records · Page 3Linked to original sources
PubMed1990

Tissue-specific sorting of the human LDL receptor in polarized epithelia of transgenic mice.

The distribution of human low density lipoprotein (LDL) receptors was studied by immunofluorescence and immunoelectron microscopy in epithelial cells of transgenic mice that express high levels of receptors under control of the metallothionein-I promoter. In hepatocytes and intestinal epithelial cells, the receptors were confined to the basal and basolateral surfaces, respectively. Very few LDL receptors were present in coated pits or intracellular vesicles. In striking contrast, in the epithelium of the renal tubule the receptors were present on the apical (lumenal) surface where they appeared to be concentrated at the base of microvilli and were abundant in vesicles of the endocytic recycling pathway. Intravenously administered LDL colloidal gold conjugates bound to the receptors on hepatocyte microvilli and were slowly internalized, apparently through slow migration into coated pits. We conclude that (a) sorting of LDL receptors to the surface of different epithelial cells varies with each tissue; and (b) in addition to a signal for clustering in coated pits, the LDL receptor may contain a signal for retention in noncoated membrane that is manifest in hepatocytes and intestinal epithelial cells, but not in renal epithelial cells or cultured human fibroblasts.

Animals↗
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

Multiple receptors for modified low density lipoproteins in mouse peritoneal macrophages: different uptake mechanisms for acetylated and oxidized low density lipoproteins.

Receptor-mediated incorporations of two modified low density lipoproteins (LDL), acetylated LDL (acetyl-LDL) and oxidized LDL were compared in vitro in mouse peritoneal macrophages by cross-competition experiments. Excess amount of oxidized LDL inhibits the binding of [125I]acetyl-LDL only partially, and excess amount of acetyl-LDL inhibits that of [125I]oxidized LDL also only partially, suggesting that the uptake of the two LDL by macrophages is mediated by partially overlapped yet different mechanisms. Scatchard analysis of [125I]acetyl-LDL binding showed a linear plot and addition of excess amount of oxidized LDL partially displaced the binding sites without changing the affinity, suggesting that there are two classes of receptors with similar affinity; one is specific for acetyl-LDL and the other is common. And the plot of [125I]oxidized LDL binding showed a curvilinear plot and excess amount of acetyl-LDL partially displaced the binding sites of the low affinity, suggesting that there are two classes of binding sites with different affinities and the low affinity one is shared with acetyl-LDL. These results indicate that macrophage receptors for modified LDL consist of at least three receptors, two of which are specific for each LDL and the rest is a common receptor.

Acetylation↗
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

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

Cholesteryl ester accumulation in macrophages incubated with low density lipoprotein pretreated with cigarette smoke extract.

Although cigarette smoking is one of the major risk factors for atherosclerosis and coronary heart disease, the precise mechanisms of its adverse effects have not been fully elucidated. We incubated low density lipoprotein (LDL) with cigarette smoke (CS) extract and examined the incorporation of the lipoprotein by macrophages in vitro. When incubated with macrophages, LDL pretreated with CS extract (100 micrograms/ml) stimulated cholesteryl [14C]oleate synthesis approximately equal to 12.5-fold that with unmodified LDL and transformed macrophages to cells rich in lipid droplets positively stained with oil red O. Enhancement in cholesteryl ester synthesis was dependent on the concentration of CS-modified LDL and exhibited saturation kinetics. When subjected to electrophoreses, CS-modified LDL migrated to a more anionic position than did unmodified LDL and showed extensive fragmentation of apolipoprotein B. This LDL modification depended upon the incubation time and concentration of the CS extract. Superoxide dismutase inhibited modification of LDL by 52%, suggesting that superoxide anion is, at least in part, involved. These results suggest that CS extract alters LDL into a form recognized and incorporated by macrophages. Such modification if it occurs in vivo, could explain the increased incidence of atherosclerosis and coronary heart disease in smokers.

Animals↗
PubMed1988

Stimulated arachidonate metabolism during foam cell transformation of mouse peritoneal macrophages with oxidized low density lipoprotein.

Changes in arachidonate metabolism were examined in mouse peritoneal macrophages incubated with various types of lipoproteins. Oxidized low density lipoprotein (LDL) was incorporated by macrophages and stimulated macrophage prostaglandin E2 (PGE2) and leukotriene C4 syntheses, respectively, 10.8- and 10.7-fold higher than by the control. Production of 6-keto-PGF1 alpha, a stable metabolite of prostacyclin, was also stimulated. No stimulation was found with native LDL, which was minimally incorporated by the cells. Acetylated LDL and beta-migrating very low density lipoprotein (beta-VLDL), though incorporated more efficiently than oxidized LDL, also had no stimulatory effect. When oxidized LDL was separated into the lipoprotein-lipid peroxide complex and free lipid peroxides, most of the stimulatory activity was found in the former fraction, indicating that stimulation of arachidonate metabolism in the cell is associated with uptake of the lipoprotein-lipid peroxide complex. These results suggest that peroxidative modification of LDL could contribute to the progression of atheroma by stimulating arachidonate metabolism during incorporation into macrophages.

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

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↗
PubMed1986

Stimulation of cholesteryl ester synthesis in mouse peritoneal macrophages by cholesterol-rich very low density lipoproteins from the Watanabe heritable hyperlipidemic rabbit, an animal model of familial hypercholesterolemia.

Cholesterol-rich very low density lipoproteins (VLDL) from the homozygous Watanabe heritable hyperlipidemic (WHHL) rabbit induced marked cholesteryl ester accumulation in mouse peritoneal macrophages. This WHHL rabbit, an animal model of human familial hypercholesterolemia, has severe hypercholesterolemia, cutaneous xanthomas, and fulminant atherosclerosis due to the deficiency of the low density lipoprotein (LDL) receptor. When incubated with mouse peritoneal macrophages, the VLDL from WHHL rabbit (WHHL-VLDL) stimulated cholesteryl [14C]oleate synthesis 124-fold more than did VLDL from the normal Japanese White rabbit (control-VLDL). The enhancement in cholesteryl ester synthesis and accumulation of WHHL-VLDL was due to the presence of a high affinity binding receptor site on the macrophage cell surface that mediated the uptake and lysosomal degradation of WHHL-VLDL. Competition studies showed that the uptake and degradation of 125I-WHHL-VLDL was inhibited by unlabeled excess WHHL-VLDL and beta-migrating VLDL (beta-VLDL), but not LDL. Furthermore, the degradation of WHHL-VLDL was not blocked by either fucoidin, polyinosinic acid, or polyguanylic acid, potent inhibitors of the acetylated (acetyl)-LDL binding site, or by acetyl-LDL. These results suggest that macrophages possess a high affinity receptor that recognizes the cholesterol-rich VLDL present in the plasma of the WHHL rabbit and that the receptor which mediates ingestion of WHHL-VLDL seems to be the same as that for beta-VLDL and leads to cholesteryl ester deposition within macrophages. Thus the uptake of the cholesterol-rich VLDL from the WHHL rabbit by macrophages in vivo may play a significant role in the pathogenesis of atherosclerosis in the WHHL rabbit.

Animals↗
PubMed1983

[Two-dimensional echo-cardiographic study on left atrial thrombi in patients with a mitral prosthetic valve].

Two-dimensional echocardiographic study was performed to detect left atrial thrombi in 33 patients with a prosthetic mitral valve. The subjects were 9 males and 24 females and their ages ranged from 21 to 61 years (average 43.2 years). Their prosthetic valves consisted of 18 Hancock, three Carpentier-Edwards, four Björk-Shiley, four Starr-Edwards and four St. Jude Medical valves. Two-dimensional echocardiograms were obtained using a Toshiba SSH-11A echograph with an electronic phased-array scanner. The left parasternal, apical, subcostal and right parasternal windows were used to detect left atrial thrombi. In five of the 33 patients, a left atrial thrombus was demonstrated as a mass echo attached to the posterior wall of the left atrium. The clinical and echographic features of five patients with a left atrial thrombus (Group A) were compared to those of 28 patients without it (Group B). The average age at the time of operation was 44.6 +/- 9.7 years in Group A and 43.0 +/- 9.5 years in Group B, showing no difference between the two groups. In 10 of the 33 patients, a left atrial thrombus was confirmed by the initial operation. In only one of these 10 patients, a left atrial thrombus was demonstrated by post-operative two-dimensional echocardiographic examination. The presence or absence of a left atrial thrombus in the pre-operative stage did not clearly relate to the occurrence of a left atrial thrombus in the post-operative stage. The cardio-thoracic ratio was significantly greater (p less than 0.01) in Group A (74.4 +/- 6.3%) than in Group B (58.1 +/- 8.1%). Left atrial dimension by M-mode echocardiograms was significantly greater (p less than 0.05) in Group A (70.6 +/- 11.3 mm) than in Group B (51.6 +/- 7.7 mm). The length of the pseudo-septalized left ventricular posterior wall was longer (p less than 0.05) in Group A (34.0 +/- 11.5 mm) than in Group B (12.8 +/- 9.4 mm). The angle between the perpendicular to the mitral annulus and the upper part of the interventricular septum was significantly greater (p less than 0.01) in Group A (58.6 +/- 18.0 degrees) than in Group B (18.8 +/- 9.6 degrees). The characteristics observed in Group A were thought to be caused mainly by the giant left atrium. Therefore it is concluded that there is a close relationship between left atrial thrombi and the giant left atrium in patients with a mitral prosthetic valve.

Adult↗
PubMed1982

[Evaluation of left ventricular diastolic chamber stiffness by the apexcardiogram and echocardiogram].

This study was made to evaluate left ventricular (LV) chamber stiffness noninvasively utilizing the apexcardiogram and echocardiogram. Subjects were 13 patients with left ventricular hypertrophy (LVH) and 17 patients without LVH. Cardiac catheterization and LV angiography were also performed in all patients. In the apexcardiogram, as shown in Figs. 1 and 2, the ratios of an amplitude to the total amplitude were measured at the onset of left atrial systole (H1) (80 msec after the onset of the P wave) and the peak of A wave (H2). In the echocardiogram, LV internal diameters were determined at 80 msec after the onset of the P wave (D1) and the peak of the R wave of ECG (D2). In addition left ventricular volumes, V1 and V2, were calculated by D1 and D2 using Teichholz's method. Increments of the ratio of an amplitude of the ACG wave (delta H = H2-H1) and LV volume changes (delta V = V2-V1) which are associated with left atrial systole were calculated. The ratio of delta H to delta V (delta H/delta V) was defined as a measure of LV diastolic chamber stiffness. On the other hand, various parameters (delta P/delta V, K, dV/dP, dV/VdP) which represent LV diastolic properties were determined by LV pressure curves and LV cineangiograms. delta H/delta V by noninvasive method showed good correlations with delta P/delta V (r = 0.83), K (r = 0.68), dV/dP (r = -0.80) and dV/VdP (r = -0.75), respectively. The correlations were much better between delta H/delta V and these parameters than between A/Eo and these parameters. Patients with LVH had much greater diastolic stiffness (delta H/delta V = 2.03 +/- 1.10) than those without LVH (delta H/delta V = 0.60 +/- 0.29, p less than 0.01). It is concluded that delta H/delta V obtained from ACG and the echocardiogram is a useful parameter to evaluate LV diastolic chamber stiffness noninvasively and this ratio is well correlated with LVH.

Adolescent↗