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Biomedical subjects

M Shiomi

Publications and source records attributed to M Shiomi.

At least 19 recordsLinked to original sources
PubMed2001

MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion.

To examine whether a microsomal triglyceride transfer protein (MTP)-inhibitor is effective in patients with homozygous familial hypercholesterolemia, we administered (2S)-2-cyclopentyl-2-[4-[(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)methyl]phenyl]-N-[(1S)-2-hydroxy-1-phenylethyl]ethanamide (Implitapide), a new MTP inhibitor, to low-density lipoprotein (LDL)-receptor-deficient Watanabe heritable hyperlipidemic (WHHL) rabbits at doses of 3, 6, and 12 mg/kg for 4 weeks. In the 12 mg/kg group, the plasma cholesterol and triglyceride levels were decreased by 70% and 45%, respectively, and the very low-density lipoprotein (VLDL) secretion rate was decreased by 80%. The composition of newly secreted VLDL was similar in each group. This suggests that Implitapide diminished the number of VLDL particles secreted from the liver. Although the ratio of vitamin E/LDL was not altered by Implitapide, triglyceride accumulation and a decrease in vitamin E were observed in the liver. In conclusion, an inhibition of VLDL secretion led to a decrease of plasma LDL in WHHL rabbits, and MTP inhibitors should have hypolipidemic effects against homozygous familial hypercholesterolemia.

Animals↗
PubMed2001

Heme oxygenase-1 inhibits atherogenesis in Watanabe heritable hyperlipidemic rabbits.

BACKGROUND: Heme oxygenase-1 (HO-1) is proposed to have a variety of adaptive responses against oxidative stress. To examine the function of HO-1 against atherogenesis in vivo, we observed the effects of HO-1 inhibition on atherosclerotic lesion formation in Watanabe heritable hyperlipidemic rabbits (WHHL). Methods and Results- During 4 weeks of a 1% cholesterol diet, intravenous injections of Sn-protoporphyrin IX to inhibit HO-1 (S group, n=10) and saline as a control (C group, n=10) were given to 3-month-old WHHL rabbits. The percentages of en face atherosclerotic lesion areas in total descending aorta by Sudan IV staining (EFA) and the ratio of intima to media in microscopic atherosclerotic lesions in the ascending aortas (I/M) were calculated. Two different quantitative methods revealed significantly greater atherosclerotic lesions in the S group than the C group (EFA, P<0.001; I/M, P<0.005). HO-1 expression in atherosclerotic lesions was confirmed by Northern blot and immunohistochemical analyses. The dominant cell types expressing HO-1 were macrophages and foam cells, in which oxidized phospholipids were also accumulated. HO inhibition increased plasma and tissue lipid peroxide levels without affecting plasma lipid co osition. CONCLUSIONS: These results suggest the possibilities that HO-1 has antiatherogenic properties in vivo and that the antiatherogenic properties of HO-1 are conducted through the prevention of lipid peroxidation.

Animals↗
PubMed2001

Serotonin-induced hypercontraction through 5-hydroxytryptamine 1B receptors in atherosclerotic rabbit coronary arteries.

BACKGROUND: Augmented vasoconstriction to serotonin (5-hydroxytryptamine [5-HT]) in atherosclerotic vessels plays a crucial role in the development of myocardial ischemia. We investigated mechanisms for serotonin-evoked hypercontraction in atherosclerotic rabbit coronary arteries. METHODS AND RESULTS: Contractile responses to serotonergic agents of endothelium-denuded coronary arteries from control and Watanabe heritable hyperlipidemic rabbits (WHHL) were examined. WHHL coronary arteries exhibited hypercontraction to 5-HT(1)-receptor agonists; the constrictor threshold concentrations and E:D(50) to serotonin, 5-carboxamidotryptamine, and sumatriptan in WHHL were significantly lower, and the E:(max) in WHHL to these agents were increased 55% to 59% above those of the control. Serotonin-evoked contractions in both groups were inhibited by GR127935 (5-HT(1B/1D) antagonist; 0.1 to 1 nmol/L) and pertussis toxin but not by ketanserin (5-HT(2) antagonist; 0.01 to 1 micromol/L), suggesting that the hypercontraction is most likely mediated by 5-HT(1B/1D) receptors through a pertussis toxin-sensitive pathway. Furthermore, simultaneous measurements of [Ca(2+)](i) and isometric tension of fura-2-loaded arteries revealed that the hypercontraction was concomitant with the augmented elevation of [Ca(2+)](i) in the smooth muscle. The 5-HT(1B) mRNA levels in WHHL coronary arteries increased to 2.5-fold over those in control arteries, whereas neither 5-HT(1D) nor 5-HT(2A) mRNA was detected in either group. CONCLUSIONS: Atherosclerotic rabbit coronary arteries exhibited the enhancement in contraction and Ca(2+) mobilization in response to serotonin. The 5-HT(1B) receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin.

Animals↗
PubMed2001

Statins alter smooth muscle cell accumulation and collagen content in established atheroma of watanabe heritable hyperlipidemic rabbits.

BACKGROUND: Acute coronary syndromes often result from rupture of vulnerable plaques. The collagen content of plaques probably regulates their stability. This study tested whether HMG-CoA reductase inhibitors (statins) alter interstitial collagen gene expression or matrix metalloproteinase (MMP) levels in rabbit atheroma. METHODS AND RESULTS: We administered equihypocholesterolemic doses of pravastatin (a hydrophilic statin, 50 mg. kg(-1). d(-1), n=9), fluvastatin (a cell-permeant lipophilic statin, 20 mg. kg(-1). d(-1), n=10), or placebo (n=10) to mature Watanabe heritable hyperlipidemic rabbits for 52 weeks. The fluvastatin group achieved a much higher peak plasma concentration (23.7 micromol/L) than did the pravastatin group (1.3 micromol/L) under these conditions. Immunohistochemistry revealed that MMP-1, MMP-3, and MMP-9 expression by macrophages in the intima was lower in both the pravastatin and fluvastatin groups than in the placebo group, whereas there was no difference in macrophage numbers. Numbers of intimal smooth muscle cells (SMCs) (identified by immunohistochemistry) and expression of type I procollagen mRNA (detected by in situ hybridization), however, were significantly higher in the pravastatin group than in the fluvastatin group. Treatment with pravastatin, but not fluvastatin, preserved interstitial collagen content in vivo (detected by picrosirius red polarization). In vitro, fluvastatin, but not pravastatin, decreased numbers of rabbit and human aortic SMCs without altering procollagen I mRNA expression. CONCLUSIONS: This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo.

Animals↗
PubMed2001

An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro.

BACKGROUND: Unstable atherosclerotic plaques that cause acute coronary events usually contain abundant macrophages expressing matrix metalloproteinases (MMPs) and tissue factor (TF), molecules that probably contribute to plaque rupture and subsequent thrombus formation. Lipid lowering with HMG-CoA reductase inhibitors reduces acute coronary events. METHODS AND RESULTS: To test whether lipid lowering with an HMG-CoA reductase inhibitor retards macrophage accumulation in rabbit atheroma, we administered cerivastatin to immature Watanabe heritable hyperlipidemic rabbits (cerivastatin group, n=10, cerivastatin 0.6 mg x kg(-1) x d(-1); control group, n=9, saline 0.6 mL x kg(-1) x d(-1)) for 32 weeks and measured macrophage accumulation and expression of MMPs and TF. Serum cholesterol levels after 32 weeks were 809+/-40 mg/dL (control group) and 481+/-24 mg/dL (treated group). Cerivastatin diminished accumulation of macrophages in aortic atheroma. Macrophage expression of MMP-1, MMP-3, MMP-9, and TF also decreased with cerivastatin treatment. Cerivastatin reduced the number of macrophages expressing histone mRNA (a sensitive marker of cell proliferation) detected by in situ hybridization but did not alter macrophages bearing a marker of death (TUNEL staining). Cerivastatin treatment (>or=0.01 micromol/L) also reduced growth, proteolytic activity due to MMP-9, and TF expression in cultured human monocyte/macrophages. CONCLUSIONS: These results suggest that lipid lowering with HMG-CoA reductase inhibitors alters plaque biology by reducing proliferation and activation of macrophages, prominent sources of molecules responsible for plaque instability and thrombogenicity.

Animals↗
PubMed2001

Gene expression analysis in colorectal cancer using practical DNA array filter.

PURPOSE: We examined the usability of a newly developed, compact-sized DNA array filter for studying the gene expression pattern of individual colorectal cancer. METHODS: Complementary DNA probes were prepared from mRNA extracted from colonic cancer specimens and adjacent normal mucosa and then were labeled with chemiluminescence. These labeled probes were allowed to bind to the gene fragments on the filter. A specialized scanning charge-coupled device camera measured the intensity of each chemiluminescent spot, which is an indicator of the degree to which a specific gene is expressed. Gene expression image was quantified into intensity of signals by using computer software. RESULTS: Characteristic gene expression patterns were obtained from the colonic cancer cell line, RPMI4788, and the leukemia cell line, HL60, by using this compact-sized DNA array filter in the preliminary experiment. Up-regulation of nm23, TIMP1, VEGF, and cyclin E and down-regulation of some tumor suppressor genes (p53, TOSO, and SIVA), beta-catenin, and metallothionein were observed in colonic cancer specimen when compared with those of normal mucosa. CONCLUSIONS: We have obtained unique gene expression patterns from colorectal cancer and normal tissue by using a newly developed compact-sized DNA array filter system. Collecting, storing, and analyzing of gene expression data from many samples of colorectal cancer will enable us to identify distinct subsets of patients based on molecular characteristics in the near future.

Cell Line↗
PubMed2001

Cerebral atherosclerosis occurs spontaneously in homozygous WHHL rabbits.

We demonstrated that selectively bred homozygous WHHL rabbits known to show hypercholesterolemia and severe coronary atherosclerosis also spontaneously develop cerebral atherosclerosis beginning at 9 months of age. These intracranial lesions occurred in the absence of hypertension in 24 of 25 animals at various sites, mainly along arteries at the base of the brain. No lesions were observed in penetrating arteries. Lesions were rich in smooth muscle cells and fibrous tissue, showing only rare fragmentation or disappearance of the internal elastic lamina, and only limited lipid deposition. Few macrophages were observed in these lesions. No significant correlation was seen between severity of cerebral atherosclerosis and age, systolic blood pressure (BP), serum total cholesterol, or triglyceride concentration. Xanthomas of the pia mater were observed in all 25 rabbits. Arterial findings were similar to those in human cerebral atherosclerosis, indicating that the coronary atherosclerosis-prone homozygous WHHL rabbit represents the first animal model for spontaneous cerebral atherosclerosis.

Aging↗
PubMed2001

Fibromuscular cap composition is important for the stability of established atherosclerotic plaques in mature WHHL rabbits treated with statins.

We examined the relationship between plaque vulnerability and fibromuscular cap composition using hydrophilic pravastatin and lipophilic fluvastatin. WHHL rabbits aged 10 months were given pravastatin (50 mg/kg) or fluvastatin (20 mg/kg) for 52 weeks. The atherosclerotic lesions were immunohistochemically or conventionally stained and the components were analyzed with a color image analyzer. Compared with the control group, the plasma cholesterol levels were decreased by about 25% in both statin groups. Pravastatin decreased the lipid components (macrophages+extracellular lipids) in whole aortic plaques by 34% and the fibrous caps of coronary plaques by 55%. Fluvastatin decreased the fibromuscular components (smooth muscle cells+collagen fibers) in whole aortic plaques and in the fibromuscular caps of the aortic and coronary plaques. In the pravastatin group, the vulnerability index, the ratio of (lipid components)/(fibromuscular components), was decreased in whole aortic plaques by 28% and in the fibromuscular caps of coronary lesions by 61%, while the indexes were increased in the fluvastatin group. The incidence of vulnerable plaques was decreased by 74% in the coronary plaques of the pravastatin group. Our results suggest that the stability of atheromatous plaques was improved due to a decrease of the lipid components and vulnerability index of the fibromuscular cap by pravastatin.

Animals↗
PubMed2001

Hepatocellular carcinoma with biliary tumor thrombi: aggressive operative approach after appropriate preoperative management.

BACKGROUND: The aim of this study was to clarify clinicopathologic characteristics of, and to evaluate an aggressive treatment strategy for, hepatocellular carcinoma with biliary tumor thrombi. METHODS: From 1980 to 1999, a total of 132 patients underwent hepatectomy for hepatocellular carcinoma. Of these, 17 patients had macroscopic biliary tumor thrombi and were retrospectively analyzed. RESULTS: The operative procedures included right hepatic trisegmentectomy (n = 1), right or left hepatic lobectomy (n = 11), and segmentectomy or subsegmentectomy (n = 5). In 13 patients, tumor thrombi extended beyond the hepatic confluence and was treated by thrombectomy through a choledochotomy in 8 patients and extrahepatic bile duct resection and reconstruction in 5 patients. The 3- and 5-year survival rates were 47% and 28%, respectively, with a median survival time of 2.3 years. These survival rates were similar to those achieved in 115 patients without biliary tumor thrombi. In a multivariate analysis, expansive growth type and solitary tumors were independent prognostic variables for favorable outcome after operation, whereas biliary tumor thrombi was not a significant prognostic factor. CONCLUSIONS: Surgery after appropriate preoperative management of hepatocellular carcinoma with biliary tumor thrombi yields results similar to those of patients without biliary involvement. Hepatectomy with thrombectomy through a choledochotomy appears to be as effective as a resection procedure.

Bile Duct Neoplasms↗
PubMed2001

Enhanced atherosclerosis in Lp(a) WHHL transgenic rabbits.

High lipoprotein(a) [Lp(a)] levels form a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentrations is significantly increased in patients who also have high levels of LDL cholesterol. Although the relation between Lp(a) and atherosclerosis has been reported in numerous studies, little is known about whether Lp(a) would exacerbate the complicated lesion formation in vivo. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated WHHL transgenic rabbits expressing human apolipoprotein (a) and compared the atherosclerotic lesions with those of nontransgenic WHHL rabbits.

Animals↗
PubMed2001

Stability of atheromatous plaque affected by lesional composition: study of WHHL rabbits treated with statins.

We examined how lesional composition is related to the stability of coronary plaques. WHHL rabbits (12 months old) were given pravastatin and fluvastatin orally for 52 weeks. Both statins decreased plasma cholesterol levels by about 25%, but the suppressive effects on the degree of coronary plaques were mild. Macrophage (Mphi) contents in fibromuscular cap regions were decreased by pravastatin, and smooth muscle cell (SMC) contents in those were decreased by fluvastatin. The plaque vulnerability index was low in Mphi)-poor plaques, but high in SMC-poor plaques. Our results suggest that reduction in M(phi)s in the fibromuscular cap is related to plaque stabilization and that reduction in SMCs in the fibromuscular cap is related to plaque destabilization.

Animals↗
PubMed2001

Arteriosclerosis in the influx and intravisceral arteries of the liver, kidney and lung of WHHL rabbits.

We performed a histopathological investigation on arteriosclerotic development in the influx and intravisceral arteries of the liver, kidney and lung of male WHHL rabbits. In the influx arteries of these organs, we observed severe atherosclerotic vascular lesions with high-grade luminal stenosis. In the intravisceral arteries of the liver and kidney, no arteriosclerotic lesions were observed. However, in the intrapulmonary arteries, we recognized severe atherosclerotic vascular changes with high-grade stenosis or total obstruction of the lumen in some middle to large sized pulmonary arteries. These observations indicate that the development of arteriosclerosis in parenchymatous organs differs, and that some organs are predisposed to arteriosclerosis formation.

Animals↗
PubMed2001

A novel approach to ex vivo gene therapy for familial hypercholesterolemia using human amniotic epithelial cells as a transgene carrier.

This study has demonstrated the potential of human amniotic epithelial cells (HAEC) as a transgene carrier to treat patients with familial hypercholesterolemia (FH). One approach to liver-directed gene therapy is represented by transplantation of autologous hepatocytes that have been genetically modified in vitro. However, the hepatocytes must be isolated from surgically resected tissue and it is difficult to expand the hepatocytes in culture. In contrast, the advantages for using HAEC are the higher availability and the nonimmunogenicity after allotransplantation. Our strategy involved isolating HAEC from an amnion, transducing a human low-density lipoprotein receptor (LDLR) gene into these cells with a recombinant adenovirus, and transplanting the genetically modified cells into the liver of an animal model of FH. Each animal, treated with the LDLR-transduced HAEC, exhibited a substantial decrease in serum cholesterol with an eventual return to pretreatment level. Moreover, the transplanted HAEC migrated out of the sinusoids into the hepatic parenchyma and expressed the LDLRs until at least 20 days after transplantation. However, the transplanted HAEC markedly decreased in number after 10 days post-transplant with an increase of inflammatory cells. The temporary nature of the metabolic improvement may be associated with xenograft rejection and transient function of the adenoviral vector.

Adenoviruses, Human↗
PubMed2001

Foam cell formation containing lipid droplets enriched with free cholesterol by hyperlipidemic serum.

A monoclonal antibody, ASH1a/256C (256C), which binds to atherosclerotic lesions in Watanabe heritable hyperlipidemic rabbit (WHHL) aorta in vivo, recognizes complex structures of phosphatidylcholine mixed with neutral lipids. In the present study, a cell culture system is described in which foam cells express 256C-positive lipid droplets. J774.1 macrophages were incubated in the presence of a small volume of WHHL serum for 24 h to produce foam cells, which were then incubated without the WHHL serum for 3 days. Oil red O-positive lipid droplets appeared on day 1, and were present in the cells during the whole incubation period. The lipid droplets in the cells were positively immunostained with antibody 256C on day 4, although they were negative on day 1. Expression of the antigenic lipid droplets was also induced by the addition of acetylated LDL or sera from patients with hyperlipidemia. When foam cells were induced by the addition of WHHL serum, cellular content of cholesteryl ester was greatly increased but then decreased to near basal levels by day 4. Concomitantly, cellular free cholesterol increased during the culture period, indicating that the cholesteryl ester changes to free cholesterol by day 4. The lipid droplets in the foam cells on day 4 were positively stained with filipin, a fluorescent probe for free cholesterol, as well as with 256C antibody, indicating that free cholesterol is enriched in antigenic lipid droplets. These observations suggest that hydrolysis and rearrangement of cellular cholesterol take place in foam cells to form complex structures of phosphatidylcholine and free cholesterol in lipid droplets.

Animals↗
PubMed2000

Preliminary evaluation of [1-11C]octanoate as a PET tracer for studying cerebral ischemia: a PET study in rat and canine models of focal cerebral ischemia.

Octanoate is taken up into the brain and is converted in astrocytes to glutamine through the TCA cycle after beta-oxidation. We speculate that [1-11C]octanoate may be used as a tracer for astroglial functions and/or fatty acid metabolism in the brain and may be useful for studying cerebral ischemia. In the present study we investigated brain distribution of [1-11C]octanoate and compared it with cerebral blood flow (CBF) by using rat and canine models of middle cerebral artery (MCA) occlusion and a high resolution PET. In rats brain distribution of [15O]H2O measured 1-2 h and 5-6 h after insult was compared with that of [1-11C]octanoate measured 3-4 h after insult. Radioactivity ratios of lesioned to normal hemispheres determined with [15O]H2O were lower than those determined with [1-11C]octanoate. These results were confirmed by a study on a canine model of MCA-occlusion. Twenty-four hours after insult, CBF decreased in the MCA-territory of the occluded hemisphere, whereas normal or higher accumulation of [1-11C]octanoate was observed in the ischemic regions. The uptake of [1-11C]octanoate-derived radioactivity therefore increased relative to CBF in the ischemic regions, indicating that [1-11C]octanoate provides functional information different from CBF. In conclusion, we found that [1-11C]octanoate is a potential radiopharmaceutical for studying the pathophysiology of cerebral ischemia.

Animals↗
PubMed2000

Age-associated decrease in plasma cholesterol and changes in cholesterol metabolism in homozygous Watanabe heritable hyperlipidemic rabbits.

We examined the cholesterol metabolism of homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model deficient in low-density lipoprotein (LDL) receptors, to clarify the mechanism of the age-associated decrease of plasma total cholesterol, one of the properties of WHHL rabbits. The rabbits were examined at several ages: after weaning at 3 months, at sexual maturation at 6 months, at 12 months, and at 24 months, equivalent to about 35 years of age in humans. Plasma total cholesterol, triglyceride, and phospholipid levels decreased with aging by about 45%. These reductions were mainly dependent on a decrease in the LDL fraction. In the liver microsomal fraction, although there were no age-related changes in the cholesterol concentration and cholesterol 7alpha-hydroxylase (C7H) activity, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity increased and acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity decreased with aging. The lipolytic activity varied with aging. The secretion rate of very-low-density lipoprotein (VLDL) cholesterol as determined by injection of Triton WR-1339 decreased significantly with aging, while the catabolic rate of VLDL cholesterol was about 2-fold higher in the oldest group versus the young groups. From these results, we conclude that the age-associated decrease in plasma cholesterol in WHHL rabbits is related not only to a decrease in the secretion rate of VLDL cholesterol but also to an increase in the catabolic rate.

Aging↗