The VLDL receptor is made up of five functional domains that resemble the LDL receptor. In mammals, the receptor is highly expressed in muscle and fat cells, while in chicken, it is abundant in oocytes. The extremely high degree of amino acid conservation of the VLDL receptor during the evolution suggests that the receptor plays an essential role in vertebrates. Recent studies on the chicken VLDL receptor revealed that the receptor plays a key role in the uptake of yolk precursors in oocytes and mediates the growth of oocytes. The VLDL receptor is an essential receptor in avian species and the receptor-deficient mutant hens are sterile and exhibit severe hyperlipidemia with aortic atherosclerosis.J Atheroscler Thromb, 1996 ; 2 : 71-75.
We investigated the mechanism by which granulocyte-macrophage colony-stimulating factor (GM-CSF) lowers plasma cholesterol levels. Recombinant human GM-CSF (rhGM-CSF) was administered to normal and Watanabe heritable hyperlipidemic (WHHL) rabbits. Treatment with rhGM-CSF reduced the levels of cholesterol and triglyceride in these animals. In vitro colony assay for hematopoietic progenitors indicated that rhGM-CSF was capable of supporting granulocyte-macrophage colony formation in rabbits, suggesting that rhGM-CSF stimulates macrophage function even in rabbits. Northern blot analysis of rabbit very-low-density lipoprotein (VLDL) receptor showed that rhGM-CSF elevated the levels of VLDL receptor mRNA 2.6-and 1.8-fold in muscles of normal and WHHL rabbits, respectively, 1.5 hours after a single injection. Increases of 1.5-and 1.4-fold were observed in muscles of these rabbits after 5 days of administration. No changes were found in the LDL receptor mRNA levels in liver, spleen or bone marrow. These findings show that the lowering of lipids by GM-CSF may be mediated through the up-regulation of the VLDL receptor mRNA and the enhancement of macrophage function.J Atheroscler Thromb, 1996 ; 2 : 76-80.
Heparin administration to diabetic rats caused no change in VLDL, an increase in IDL and a decrease in LDL on electrophoretic analysis of plasma lipoproteins, while the administration to control rats markedly decreased VLDL and increased IDL and LDL. Both hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL) activities in the postheparin plasma were lower in the diabetic rats than in the controls, and the reduction of HTGL activity was greater than that of LPL activity in the diabetic rats. The LPL activity in the adipose tissue was lower in the diabetic rats than in the controls, but the activities in the cardiac and skeletal muscles were similar in the two rats. The HTGL-catalyzed fatty acid (FA) releases from the diabetic VLDL and IDL were lower than those from the normal rat VLDL and IDL, while the LPL-catalyzed FA release in the diabetic rats was not different from those in the controls. The decreases in LPL and HTGL activities and the markedly impaired susceptibility of IDL to HTGL coincide well with the postheparin changes in plasma lipoproteins in diabetic rats, an increase in IDL and a decrease in LDL. J Atheroscler Thromb, 1996 ; 2 : 87-95.
Lp (a) levels are genetically determined and remain stable without major changes throughout lives. However, when an individual 's Lp (a) levels are observed over a one-year period, they show spontaneous variation. The rate of intraindividual variation in Lp (a) was observed in 16 patients with hypertension, hyperlipidemia and/or glucose intolerance in a chronic stable state who regularly visited the hospital clinic once a month, at least 10 times during the year, and in whom a total of 42 blood and clinical chemistry tests including serum lipids, Lp (a) and apoproteins were performed. The rate of annual intraindividual variation of Lp (a) averaged out as 16.6%. The rate was 18.8% for isoform S4 (n =10), 18.6% for S3 (n = 3), and although small in number of subjects, other isoforms showed minor variation rates. There was a significant negative correlation between the rate of variation (y%) and Lp (a) level (xmg/dI) (r-0.605, p< 0.05, y=-0.461x+29.8). Therefore, when Lp (a) was high, the rate of variation (SD%) was low. This was consistent with the finding that the rates of variation were low for isoforms S2, S3S4 and F, whose molecular weights were low, accompanied by high Lp (a) levels. On the other hand, when the relationship between Lp (a) level and the amount of variation (SD mg/dl) was examined, there was no correlation between the two, since the amounts of variation were almost constant at a level of 3.8 mg/dl, regardless of Lp (a) level. The annual variation of Lp (a) level was found to be related to three groups of factors based on comparison of the variations among WHO phenotypes of hyperlipidemias, univariate correlation analysis with the clinical parameters tested, and multivariate analysis : the first group of factors was related to structure and metabolism of very low-density lipoprotein such as triglycerides, phospholipids, apo C-II, E, A-II and uric acid; the second group was related to thrombosis centering on platelets; and the third group involved those in acute phase reactions represented by 1 hr and 2 hr erythrocyte sedimentation rates. J Atheroscler Thromb, 1999 ; 2 : 96-106.
The effects of eicosapentaenoic acid (EPA) on serum lipoprotein (a) (Lp (a)) and other lipid levels in patients with vascular disease were examined. The serum levels of Lp (a), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) were measured in 24 patients with vascular disease. An elevated serum Lp (a) level (39± 22 mg/dl) was noted in 9 patients, elevated total cholesterol level (263± 31 mg/dl) in 12 patients, elevated triglyceride level (240± 98 mg/di) in 10 patients and elevated LDL level (651±88 mg/dl) in 6 patients before administration of EPA. EPA (1, 800 mg/day) was given to these patients for long periods ranging from 6 to 24 months. The serum levels of Lp (a), TC, TG and LDL were lowered significantly (p< 0.05) after EPA administration for 12 and 18 months, for 6, 12, 18 and 24 months, for 18 months and for 12 and 18 months, respectively. These findings indicated that long-term administration of EPA may lower Lp (a) and serum lipids, which is beneficial for patients with various arterial diseases in terms of preventing progression of the disease. J Atheroscler Thromb, 1996 ; 2 : 107-109.
An in vivo effect of a novel synthetic Xa inhibitor, DX-9065a, was evaluated in a highly thrombogenic venous graft model. A woven Tetron tube graft was interposed in the inferior vena cava of rabbits. All the grafts were completely occluded within 5 hours after a bolus injection of heparin (50 U/kg) given just prior to the grafting. The following agents were continuously given to the respective group of rabbits for 2 h after the bolus injection of heparin; heparin (50 U/kg/ h, UFH-group), DX-9065a (0.05 mg/kg/h, DX-group) and argatroban (32μg/kg/h, MD-group). During a 5-h observation period, the anti-Xa activity in circulating blood between the UFH-and DX-group and the anti-thrombin activity between the UFH-and MD-group were not significantly different. The graft patency in the DX-group (4/4) and MD-group (4/4) was significantly better than that in the UFH-group (3/10). Ultrastructural analysis of the luminal surface of the harvested graft by scanning electron microscopy revealed the reduced formation of fibrin networks entrapping erythrocytes in the DX- and MD-group in comparison with the patent UFH-group. In conclusion, a novel synthetic Xa inhibitor DX-9065a exerts a potent in vivo antithrombotic effect, which was comparable with argatroban, a synthetic thrombin inhibitor. J Atheroscler Thromb, 1996 ; 2 : 110-116.
We developed a simple, sensitive and accurate method for assaying cellular free and total cholesterol by monitoring 4-cholesten-3-one, a conversion product of the cholesterol oxidasecatalyzed oxidation of the free cholesterol that has a strong chromophoric α, β-unsaturated ketone at 20 nm, using a high-pressure liquid chromatographic system. This method measured picomole quantities of free and total cholesterol and precisely determined their concentrations in cells (104 range) in culture using 7β-hydroxycholesterol as an internal standard. J Atheroscler Thromb, 1996 ; 2 : 117-121.
To determine the recent serum lipid levels in the general Japanese population and trends in their changes over the past 30 years, a nationwide survey of serum lipid levels was conducted in 39 institutes from various districts around Japan. The total number of subjects was 34, 815, consisting of 20, 279 men and 14, 536 women aged 4 through 99 years. All the serum samples were collected and analyzed within one week at the Special Research Laboratory (Tokyo, Japan). In males, the mean serum cholesterol level showed a gradually increase from 170 mg/dl in the 0-to 9-year-old age group to 198 mg/dl in the 50-to 59-year-old age group. There was a slight decrease after age 60 years. In females, the mean cholesterol level gradually rose with age from 173 mg/dl in the 0-to 9-year-old age group to 210 mg/dl in the 60-to 69-year-old age group, and fell to 207 mg/dl after 80 years of age. The mean HDL-cholesterol level in men gradually decreased with age from 60 mg/dl in the 0-to 9-year-old age group to 51 mg/dl in the 30-to 39-year-old age group, remained at this level up to 69 years of age, and then increased to 54 mg/dl for the above 80 years old group. The mean HDL-cholesterol level in women increased from 57 mg/dl in the 0-to 9-year-old age group to 62 mg/dl for the 20-to 29-year-old age group : then gradually decreased with age to 54 mg/dl in the 60-to 79-year-old age group. The mean LDL-cholesterol level in men gradually increased with age from 98 mg/dl in the 0-to 19-year-old age group to 122 mg/dl at 70-79 years of age. The mean LDL-cholesterol level in women was low at 101-103 mg/dl up to 29 years of age, then it increased with age to 135 mg/dl in the 60-to 69-year-old age group. The serum cholesterol levels in 1970 and 1980 were higher than that in 1960, but in 1990 values similar to those in 1960 were observed in both men and women. The present results will become the standard serum lipid level data for the Japanese people, and succeeding 10-year surveys will clarify the trends of lipid levels in this country. J Atheroscler Thromb, 1996 ; 2 : 122-132.