The effects of SR-A I/II deficiency and a synthetic anti-oxidant BO-653 on a diet-induced atherosclerosis in C57BL/6J, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, were examined. Quantitative analysis of the extent of atherosclerotic lesions in the mice fed the high-fat diet revealed that the atherosclerotic lesion area in SR-A I/II mutants was significantly reduced by 70% compared to wild type mice. A similar level of lesion reduction (75%) was found in wild type mice fed the high-fat diet supplemented with 0.6% BO-653 compared to those without BO-653. Thus, for C57BL/6J in the setting of prolonged exposure to a high-fat diet, defect of SR-A I/II expression is significantly protective against the development of atherosclerosis, as is the synthetic anti-oxidant BO-653. These results indicate that SR-A I/II has a crucial role in atherosclerotic lesion formation with uptake of oxidized-LDL in this mouse model.
We established a strategy to directly measure cholesterol and triglyceride levels of each lipoprotein fraction using a combination of agarose gel electrophoresis and differential staining. The cholesterol and triglyceride levels determined by electrophoresis correlated significantly with those of ultracentrifugation. The correlation coefficients between these methods were, for cholesterol levels 0.975 (very low density lipoproteins, VLDL), 0.986 (low density lipoproteins, LDL) and 0.965 (high density lipoproteins, HDL) and for triglyceride levels 0.994 (VLDL), 0.963 (LDL) and 0.959 (HDL) respectively. Both intra-and inter-assays showed low values of coefficients of variation (CV) (less than 3.57%). We observed a strong linearity between staining and triglyceride concentration. An increased VLDL-cholesterol was observed in type Ill subjects, a result which enabled distinction between type Ill and type llb or type V lipoproteinemia. The method revealed lipoprotein patterns in some samples otherwise unexpected from their corresponding serum lipid parameters. Analyses of these electrophoretic patterns thus provide an effective technique to classify types of hyperlipidemia defined by the WHO. Furthermore, quantitative measurement of chylomicrons, usually difficult, proved to be achievable, providing an additional analysis of postprandial hyperlipidemia and the exact measurement of LDL-cholesterol after diet. Consequently, we recommend this simple and easy method for clinical evaluation of abnormalities in lipoprotein profiles.
The purpose of the present study was to investigate the relationship between insulin resistance, sex hormones and sex hormone-binding globulin (SHBG) in regard to the serum lipid and lipoprotein profiles of 82 Japanese postmenopausal women. A multiple regression analysis for lipids, lipoproteins, and apoproteins as dependent variables was performed. All regression models included the following variables as potential independent variables BMI, percentage of body fat, waist-hip ratio, free testosterone (Free T) and SHBG. In addition, model A included insulin resistance evaluated by HOMA-R and model B included fasting insulin (FIRI). In model A, both Free T and HOMA-R were independent predictors of total-C (TC) /high-density lipoprotein-C (HDL-C) and low-density lipoprotein-C (LDL-C) /HDL-C. The BMI was independently associated with HDL-C. The Free T was a single independent predictor of TC and LDL-C. Both BMI and HOMA-R were independent predictors of triglyceride (TG). In addition, SHBG was also independently associated with apoprotein B (Apo B) and Apo B/Apo Al. In model B, FIRI was an independent predictor of lipid metabolism with similar results to those observed in model A. These results suggest that the lipid characteristics in postmenopausal women might be associated with insulin resistance and/ or hyperinsulinemia, and relative hyperandrogenicity which thus induces an increase in the amount of Free T and a decrease in the SHBG within physiological ranges.
Functional impairment of the vascular endothelium is an early event in the development of atherosclerosis, and soluble adhesion molecules in plasma are regarded as an indicator of the endothelial damage in diabetes mellitus. We compared the soluble vascular adhesion molecule levels in the patients with diabetic nephropathy in concerning with plasma 7-ketocholesterol levels, which is major cholesterol auto-oxidation products. Average value of plasma VCAM-1 in 31 patients with type 2 diabetes mellitus was 297.6±10.2 ng/ml (mean±SE), and the value was significantly higher than that in 8 age-matched healthy controls (231.9±15.0 ng/ml). Among the 31 diabetic patients, the group with macroalbuminuria (n= 8) had the higher levels of plasma VCAM-1 (349.5±26.0 ng/ml) than the levels in the group with normoalbuminuria (n=15 ; 280.6±12.3 ng/ml). The levels of plasma 7-ketocholesterol in diabetes (26.9±1.5 ng/ml) or the patients with macroalbuminuria (31.4±3.3 ng/ml) were significantly higher than the control (22.5±1.8 ng/ml). The level of soluble VCAM-1 showed significant correlation between the values of 7-ketocholesterol (r = 0.42, p = 0.024), TC (r= 0.42, p = 0.014) and LDL-C (r = 0.38, p = 0.044). However no correlation was demonstrated with HbA1c nor creatinine level. We conclude that soluble VCAM-1 in plasma may be an indicator of oxidative stress and vascular injury in diabetic nephropathy.
The effect of angiotensin converting enzyme inhibitor, temocapril hydrochloride on the serum lipoproteins, and especially on the size of low density lipoproteins (LDL) of hypertensive diabetic patients, were studied. Temocapril hydrochloride (5 mg/day) was administered to 32 hypertensive type 2 diabetes patients for 16 weeks. During treatment, systolic and diastolic blood pressures decreased significantly from 162/95 mmHg to 138/76 mmHg at 16 weeks (p< 0.001), and serum levels of total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) showed significant reduction, but those of HbA1c, triglycerides (TG) and high density lipoprotein cholesterol (HDL-C) showed no significant changes. LDL particle size evaluated by polyacrylamide gel disc electrophoresis was normalized from small size. It is concluded that temocapril hydrochloride favorably affects the serum lipoprotein metabolism of hypertensive type 2 dependent diabetes mellitus patients.
Increasing evidence has indicated the important roles of inflammation and immune response in the development of atherosclerosis and ischemic heart disease (IHD). We measured the serum interleukin (IL) -8 and IL-12 levels of patients with unstable angina pectoris (UAP) and patients with acute myocardial infarction (AMI), and compared findings with those of normal subjects. The results showed that the serum level of IL-8 was significantly higher in patients with UAP and patients with AMI than in healthy control subjects. To our knowledge, this is the first report that serum IL-12 level was elevated in patients with AMI but not in patients with UAP. These findings suggest that IL-8 and IL-12 are involved in the process of IHD, and serum IL-12 may be a marker for differentiating AMI from UAP.