LRP (LDL receptor-related protein) is considered to be one of the remnant receptors. Amino acid sequence analysis indicates that LRP is identical to the alpha2 macroglobulin receptor, which has been shown to bind and internalize following ligands; beta-VLDL with apoprotein E or lipoprotein lipase, alpha2 macroglobulin-protease complex, and plasminogen activator-inhibitor complexes. These characteristics indicate that LRP/alpha2 macro globulin receptor might be responsible in atherosclerotic lesions for foam-cell formation and regulation of protease activity. In order to investigate the role of LRP in atherogensis, we used the RT-PCR method to examine the expression of LRP mRNA in human atherosclerotic lesions.
Atherosclerotic lesions were divided into three groups: normal intima, raised lesion, and calcified lesions. From these fractions, total RNA were extracted by the AGPC method and RT-PCR was performed.
The results of PCR showed that expression of LRP mRNA was more abundant in atherosclerotic lesions than in normal intima or media, suggesting that LRP might play a role in atherosclerosis.

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The purpose of this study is to evaluate changes in hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL) as a cause of dyslipoproteinemia in hypothyroidism. Hypothyroidism is associated with pronounced hypercholesterolemia and moderate hypertriglyceridemia. Recent studies suggest that such changes in serum lipids result from the decrease in LDL-receptors and also HTGL and/or LPL activities. In order to accurately evaluate the correlation between both lipases and lipoprotein abnormalities in patients with hypothyroidism, we measured LPL and HTGL mass concentrations in postheparin plasma by means of a sandwich-enzyme immunoassay (EIA) using two distinct monoclonal antibodies before and after treatment with thyroid hormone.
Seven patients with untreated hypothyroidism and euthyroid normal controls (n=76) were studied. Hypothyroidism group (H) consisted of 3 males and 4 females (age 60±5 years) and the control group (N) of 46 males and 30 females (age 42±13 years). The plasma cholesterol (C) and triglyceride (TG) levels were significantly increased in the H group compared to the N group: 327±27 vs. 192±27ma/dl and 145±24 vs 88±33mg/dl, respectively. There was no difference in HDL-C (61.2±5.7 vs. 63.1±6.6mg/dl). HTGL was markedly reduced (79%) in the H group (264±57 vs. 1, 252±55ng/ml), while LPL was only slightly reduced (16%) (153±17 vs. 182±5ng/ml). The H group showed a hyperlipidemia of IIa (n=5) or IIb (n=2) as a WHO phenotype. After the patients were treated with thyroid hormone, HTGL level was drastically increased from 264±57ng/ml to 858±115ng/ml, and the LPL level also increased from 153±17ng/ml to 201±29ng/ml. Plasma C level decreased from 327±27 to 234±3mg/dl, and TG from 145±24 to 78±13mg/dl. By plotting all the patient data before and after the treatment, HTGL showed a positive correlation with FT₃ (r=0.86) and negative correlation with TSH (r=-0.66). HTGL showed significant inverse correlations with LDL-TG/apoB (r=-0.74) and HDL-TG/apoA (r=-0.74). Our data indicates that HTGL mass concentration is regulated by thyroid hormone level leading us to conclude that HTGL is closely related to the metabolism of triglyceride-rich LDL and HDL particles.

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We developed a total thymectomy model for the rabbit, and then studied the role of the thymus in experimental atherogenesis. Ten-week-old male Japanese white rabbits weighing approximately 1.9kg were used. After 26 of these rabbits underwent median sternotomy, they were divided into a thymectomy group (group Tx, n=13) and a dummy operation group (group Sx, n=13). Atherosclerosis was induced by administering a 0.5% cholesterol-rich diet, 150g daily.
At 12 weeks after the operation, the average plasma concentrations of cholesterol were 1, 454±374mg/dl in group Tx and 1, 391±388mg/dl in group Sx. The circulating lymphocyte count in group Tx did not decrease after thymectomy, and consequently, no statistically significant difference between the two groups was observed. The percentage of lipid deposition coverage in the aorta was 58.8±14.9% in group Tx and 30.7±7.7% in group Sx (p<0.01). Cholesterol content in the aortic wall was 30.7±13.2mg/g dry tissue in group Tx and 8.2±3.2mg/g dry tissue in group Sx (p<0.01).
Our results suggest that the thymus has antiatherogenic properties.

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Cerebrovascular and cardiovascular diseases are important predictors for survival in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Recently, increased levels of Lp (a) were documented in nephrotic syndrome and renal failure. We quantified the plasma levels and peritoneal loss of lipids and lipoproteins, and studied the composition of plasma and effluent lipoproteins in 19 patients on CAPD (10 females and 9 males, 26 to 73 years old). Median levels of plasma Lp (a) were significantly elevated in CAPD patients compared to controls (30.5 vs. 10.7mg/dl, P<0.05). We found no statistically significant correlations of Lp (a) with age, blood pressure, plasma lipoprotein, apoprotein, glycated hemoglobin, BUN, creatinine, plasma protein levels, or the duration of CAPD treatment. All plasma lipoproteins, (VLDL, IDL, LDL, Lp (a), and HDL) were present in the peritoneal effluent. There were significant positive correlations between plasma Lp (a) levels & peritoneal loss of Lp (a) and total cholesterol. Positive correlation was observed between peritoneal loss of Lp (a) & proteins and other lipoproteins. Autopsy material from the left coronary artery and from the thoracic aorta has been examined by means of immunohistochemistry. Most of plasma Lp (a) accumulates in the arterial wall intima. We suggest, based on our findings, that the increased hepatic synthesis of Lp (a) due to the continuous peritoneal loss of Lp (a) & proteins and/or impaired catabolism of Lp (a) contribute to the high levels of plasma Lp (a) in CAPD patients, and such factors may have led to the accelerated atherosclerosis observed in these patients.

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The Oxidative modification of low-density lipoprotein (LDL) could contribute to atherosclerosis as a result of its cytotoxic effect, uptake by the scavenger receptor, and its influence on monocyte and macrophage migration. Ascorbate is an important watersoluble, chain-breaking antioxidant in humans.
In this study, we examined the effect of ascorbate on the Cu²⁺-induced oxidative modification of LDL. LDL was incubated for 24 hours with 2.5μM copper (Cu²⁺) in phosphate-buffered saline (PBS) in both the presence and absence of ascorbic acid (20μg/ml, 25μg/ml, 30μg/ml, and 35μg/ml). Ascorbate significantly inhibited the oxidative modification of LDL, as indicated by both the decreased electrophoretic mobility and the linoleic acid content. Oxidative modification was prevented in a concentration-dependent manner by the addition of ascorbate.
Our data suggests that ascorbate may play an important physiological role in protection against the oxidative modification of LDL.

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Many epidemiological studies have indicated that Lp (a) is a potent risk factor for coronary heart disease. We have reported the elevation of Lp (a) in NIDDM, especially in subjects with nephropathy, and suggested a possible role for Lp (a) in the development of nephropathy. Herein, we investigated fluctuations in serum Lp (a) concentration induced by metabolic control, and assessed the effectiveness of niceritrol (750mg/day) therapy for hyperlipidemic NIDDM. Our findings were as follows.
1) In diabetics under stable metabolic control, Lp (a) concentration is stable over a several-month interval.
2) Neither significant amelioration or deterioration of glycemic control were associated with significant changes in Lp (a) concentration.
3) Niceritrol therapy resulted in significant decreases in Lp (a) concentrations and might be reduce the risk of diabetic vascular complications.

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To test the effect of bezafibrate on glucose metabolism in NIDDM patients, 400mg per day of bezafibrate were administrated orally for up to six months to 57 hyperlipidemic patients with NIDDM, who were under metabolic control. Serum triglyceride and total cholesterol levels decreased by 40% and 8%, respectively, after the administration of bezafibrate, although the decrease in total cholesterol was not significant after six months. Serum HDL cholesterol was increased by 15%. The fasting serum insulin level was decreased significantly after three to six months, but hemoglobin Alc, blood glucose, and free fatty acids were not affected. These findings indicate an additional effect of bezafibrate in lowering serum lipids. They also indicate an inhibition of hepatic glucose production.

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It has been reported that although the HMG-CoA reductase inhibitor, simvastatin, does not always effectively lower plasma LDL, the drug inhibits LDL oxidation. Simvastatin may therefore prevent atherosclerosis by mechanisms other than its hypocholesterolemic activity. Foam cells in atherosclerotic lesions contain large amounts of cholesterol ester. The direct effects of simvastatin on cholesterol ester accumulation and cytokine production in macrophages have not been described. In this study, we determined whether simvastatin affects cholesterol ester accumulation and cytokine production by THP-1 cells and human peripheral mononuclear cells.
Simvastatin decreased cholesterol ester accumulation without altering phospholipid accumulation in human monocyte THP-1 cells. However, free cholesterol and triglyceride levels rose slightly.
In addition, the production of cytokines was measured in THP-1 cells and human peripheral mononuclear cells stimulated by simvastatin. Simvastatin at doses ranging from 10^-9 to 10^-5 M did not affect the synthesis of proinflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) from LPS-PMA-stimulated THP-1 cells. The synthesis of IL-1α, IL-1β, IL-6 and IL-8 from human peripheral mononuclear cells was also unaffected by administration of simvastatin. In addition, any changes in cytokineinduced cytokine production (IL-1-induced IL-8 synthesis) were not detected after the addition of simvastatin. The present results suggest that simvastatin suppresses foam cell formation in monocyte/macrophages, without affecting the immunological or inflammatory function of these cells.

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The aim of this study is to clarify the effects of simvastatin on serum lipids, especially serum HDL cholesterol, in elderly and adult patients with hypercholesterolemia. Simvastatin was administrated orally in doses of 5mg per day for 7±4 months (M±SD) to 14 elderly patients aged 70±4 years and 16 adult patients aged 55±6 years. One month after initial administration, serum total cholesterol, LDL cholesterol, apolipoprotein B and atherogenic index had decreased significantly, and remained lower for an average of 7 months after administration. Levels of HDL cholesterol, apolipoprotein AI and triglyceride did not change significantly. The effects of simvastatin on serum lipids were almost identical for the elderly and adult patients.
A comparison of the predrug values and net values (i. e., postdrug—predrug) found significantly positive correlation coefficients for serum total cholesterol (r=0.41), LDL cholesterol (r=0.39), triglyceride (r=0.47) and atherogenic index (r=0.73), and a significantly inverse coefficient (r=-0.66) for HDL cholesterol. When HDL cholesterol was less than 58mg/dl initially, it tended to increase after administration of simvastatin, yielding a regression function of Y=20.9-0.36X.

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We examined histologically tissue reconstruction of rabbit thoracic aortas after balloon catheter injury in association with matrix-degrading enzymes. By light microscopic examination, tissue reconstruction with a proliferation of smooth muscle cells (SMC) was recognized only in the intima. In almost all cases, however, the media was also damaged by the catheter, which damage ended in tissue degeneration or scar formation instead of tissue remodeling as seen in the intima. There was a tendency that more marked medial damage caused more pronounced neo-intimal formation. However, in some cases in which the upper layer of the media became necrotic, thickening of the intima was rather mild. Electron microscopic observation revealed a tear or a bifurcation of the internal elastic lamina caused by the balloon catheter, suggesting that distortion of the extracellular matrix leads to migration of SMC from the media into the intima. In situ hybridization showed c-fos expression in the upper layer of the media immediately after balloon injury, and the expression was pronounced in the regenerative endothelial cells and in SMC of the fibrous plaques 3-7 days after the injury. In situ hybridization for PDGH-b by v-sis showed its strong expression in the same endothelial cells and SMC in the same sites 3-7 days after the injury. MMP-1 expression was recognized in SMC located either in the neo-intima or in the medial portion right under the internal elastic lamina. We conclude that the injury of the upper layer of the media plays an important role in the intimal reconstruction after balloon catheter treatment. Expression of MMP-1 and of some oncogenes including PDGF-b and fos is essential for the process; and in terms of PDGF expression, the improtant in this experimental model.

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