Mean Plasma Cholesterol Levels Research Articles

Abstract 444: Apolipoprotein A-I (ApoAI) Vascular Gene Therapy Protects Against Vein-Graft Atherosclerosis

Introduction: Coronary artery venous bypass grafts typically fail because of accelerated atherosclerosis, driven by lipid infiltration and by accumulation of macrophages and other cells. We previously showed that transduction of carotid artery endothelium of fat-fed rabbits with a helper-dependent adenovirus expressing apolipoprotein AI (HDAdApoAI) reduced atherosclerotic lesion size and decreased intimal lipid and macrophage accumulation. We hypothesized that HDAdApoAI transduction of rabbit vein graft endothelium would reduce lipid and macrophage accumulation. Methods: Fat-fed rabbits received bilateral external jugular vein to carotid artery interposition grafts. Four wks later, one graft per rabbit was infused with HDAdApoAI and the other with HDAdNull (a non-expressing HDAd). Grafts were harvested 12 wks after HDAd infusion. Paired analysis was performed in all rabbits with bilateral patent grafts (n=22). Graft hemodynamics were measured at vector-infusion and harvest surgeries. In vivo graft diameters were measured before vector infusion and harvest with ultrasound. Grafts were cut into 8 segments, for histology and biochemical analyses. Results: Mean plasma cholesterol levels were 400-600 mg/dL. Graft patency rates were 89% after vein grafting and 100% after the vector-infusion surgery. Lumen diameter and hemodynamics did not differ between HDAdApoAI and HDAdNull-transduced grafts. HDAd genomes were detected in all vein grafts. High levels of apoAI mRNA were detected in 100% of HDAdApoAI-treated vein grafts (mean 155-fold higher than in HDAdNull grafts). HDAdApoAI-treated grafts had 25% lower cholesterol (by mass spectrometry; P=0.03) and 17% less median CD68 mRNA (by RT-qPCR; P=0.008; CD68 is expressed by macrophages and lipid-loaded SMC). No significant differences were detected in mRNA encoding several inflammatory cytokines and inflammation-associated proteins. There were nominal decreases in total intimal area (16%, P=0.9), percent stenosis (4%, P=0.08), and in intimal area positive for Oil Red O (11%, P=0.3), macrophages (11%, P=0.7), and VCAM-1 (8%, P=0.8). Conclusion: HDAdApoAI transduction of vein graft endothelium reduces some markers of atherosclerosis, potentially by stimulating cholesterol efflux.

Blood Biochemical, Hormonal and Mineral Status of Cyclic, Acyclic, Endometriotic and Pregnant Crossbred Cows

A study was carried out on infertile (acyclic and endometriotic) crossbred cows under field and normal cyclic (all 4 phases of cycle) as well as pregnant (3, 6, 9 month) crossbred cows of University farm to evaluate the plasma progesterone (P4) and estradiol (E2) hormones by RIA, and plasma total protein, cholesterol, calcium and phosphorus concentrations by using assay kits on chemistry analyzer. The mean progesterone levels in cows during the diestrus phase and in pregnancy were significantly (p less than 0.05) higher than those during proestrus, estrus, metestrus, anestrus, and endometritis status. At six month of gestation, the mean P4 level was significantly (p less than 0.05) higher than at early or late gestation. The mean E2 values at estrus and 9th month of gestation were highest (p less than 0.01) as compared to another status. The mean plasma total protein and cholesterol levels were significantly (p less than 0.05) lower during six and nine months of pregnancy than during cyclic and acyclic stages. The cholesterol profile of all three stages of pregnancy and endometriotic cows were statistically similar, though distinctly low at 9 month of pregnancy. Plasma levels of P4 and E2 thus correlated with the physiological and clinical status of cows, while cholesterol levels reflected steroidogenic status. The mean plasma calcium and inorganic phosphorus concentrations of cyclic, acyclic, pregnant and endometriotic cows, however, did not differ significantly.

Performance of Growing Black Bengal Goats under Different Management Systems of Rearing

Thirty female Black Bengal kids were selected randomly at the age of 2 months and divided equally into three groups with having ten kids in each group and maintained from 2 to 12 month of age under three different management systems, viz., extensive, semi-intensive and intensive systems in Tripura, a North Eastern state of India. Four phenotypic variables, hematology and biochemical profiles were done every month and data were analyzed by one way ANOVA followed by Duncan's test. There was a significant (p<0.01) increase in mean (±SEM) body weight, height at withers, heart girth and body length of the goats maintained under different systems of management over the months. However, mean (±SEM) blood hemoglobin (Hb), glucose, albumin, globulin, cholesterol and alkaline phosphatase level in plasma of goats under different management systems varied significantly (p<0.05) between age groups from 2nd months to 12th months of age. Except plasma glucose level, mean (±SEM) body weight, heart girth and body length of the goats under extensive system were significantly higher (p<0.05) than those for goats maintained under semi-intensive and intensive system of management. Mean (±SEM) plasma cholesterol level in goats under extensive and semi-intensive system were more (p<0.05) than that of the goats under intensive management system. Black Bengal goats reared under extensive management system showed a better performance in terms of body weight gain, body measurements and biochemical profiles as compared to the goats reared under semi-intensive and intensive management system.

Legacy effect of statins: 20-year follow up of the West of Scotland Coronary Prevention Study (WOSCOPS).

The West of Scotland Coronary Prevention Study (WOSCOPS) was a randomized, placebo- controlled, primary prevention trial of pravastatin in men aged 45 to 64 (mean age of 55 years) with no history of myocardial infarction at randomization. A total of 6,595 men, with a mean (SD) plasma cholesterol level of 272 (23) mg/dL and mean (SD) low density lipoprotein cholesterol (LDL-C) of 192 (17) mg/dL were randomly assigned to receive pravastatin 40 mg daily or placebo for five years. The primary outcome was a composite of death from coronary heart disease (CHD) and nonfatal myocardial infarction. There was a 31% relative reduction in the primary outcome with pravastatin. There was similar reduction in risk of nonfatal myocardial infarction, death from CHD and death from all cardiovascular causes with no increased risk of death from non-cardiovascular causes nor an increase in incident cancers.

Statin Therapy for Healthy Men Identified as “Increased Risk”

ATHEROSCLEROTIC CORONARY HEART DISEASE (CHD) is the most common cause of morbidity and mortality in the world. The “lipid hypothesis” of CHD is clearly established: (1) circulating cholesterol plays a central role in atherogenesis and is an integral component of the requisite lesion, the coronary plaque; (2) cholesterol levels beginning in childhood predict lifetime risk of atherosclerotic CHD events in a dose-response relationship; and (3) statins lower cholesterol levels and reduce CHD and cerebrovascular events directly proportional to the degree of low-density lipoprotein cholesterol (LDL-C) lowering. As a result, guidelines from around the world support a combined lifestyle and pharmacologic approach to cholesterol lowering directed at patients with elevated CHD risk. Assuming a high-density lipoprotein cholesterol (HDL-C) level of about 40 mg/dL, the patient in this common clinical scenario would have an “intermediate” 10-year risk for developing CHD (approximately 10%) based on the Framingham Risk Score (FRS). As always, lifestyle change is the first-line therapy. However, if this patient’s cholesterol level remains abnormal, despite sustained attempts at lifestyle optimization, statin therapy should be considered with the goal of reducing CHD risk. Current guidelines suggest an LDL-C goal of less than 130 mg/dL with an optional target of less than 100 mg/dL. In the shared decision-making process, the clinician should explicitly inform this patient that a statin is likely to reduce the chance of a first CHD event and reduce the chance of stroke and may offer a survival benefit that is likely to become more evident over a lifetime. Evidence Supporting Primary Prevention The WOSCOPS enrolled 6595 men aged 45 to 64 years with no previous history of myocardial infarction and a mean (SD) plasma cholesterol level of 272 (23) mg/dL. Treatment with pravastatin, 40 mg, resulted in a 31% reduction in myocardial infarction and CHD-related death (248 vs 174 events and 135 vs 106 deaths for placebo vs pravastatin, respectively). Similarly, the AFCAPS/TexCAPS randomized 6605 asymptomatic adults with a mean (SD) LDL-C level of 150 (17) mg/dL and low HDL-C (36 [5] mg/dL in men and 40 [5] mg/dL in women) to lovastatin, 20 to 40 mg, vs placebo. Treatment with lovastatin reduced the incidence of first major coronary events by 37% and myocardial infarction by 40% (183 vs 116 events and 95 vs 57 myocardial infarctions for placebo vs lovastatin, respectively). The JUPITER trial enrolled 17 802 healthy men and women with so-called normal LDL-C less than 130 mg/dL and elevated high-sensitivity C-reactive protein greater than 2.0 mg/L. Aggressive lowering of LDL-C in those randomized to receive rosuvastatin, 20 mg, reduced the risk of myocardial infarction, stroke, and revascularization by about 44% (251 vs 142 events for placebo vs rosuvastatin) and total mortality by 20% (247 vs 198 events, respectively). The effect of aggressive LDL-C lowering in JUPITER was substantial considering that the baseline median LDL-C was just 108 mg/dL. Subanalysis demonstrated the largest absolute reduction in patients with a FRS of 11% to 20% (145 vs 74 events for placebo vs rosuvastatin; hazard ratio [HR], 0.51; 95% CI, 0.39-0.68) followed by those with FRS of 5% to 10% (59 vs 32 events; HR, 0.55; 95% CI, 0.36-0.84).

Effects of SOD/PEG and soy flour on insulin sensitivity of blood platelets of atherogenic dieted rabbits

The effects of antioxidant superoxide dismutase (SOD) injections and of SOD rich soybean flour were studied in New Zealand strain, male rabbits. The animals were fed an atherogenic diet (AD) of 2% Cholesterol, 6% Corn Oil and 92% Purina Rabbit Chow, for 5 weeks prior to starting the experiments using 3 experimental groups of 5 animals. Group I AD Controls –theADC group‐fed AD, Group II fed AD and injected with 2,000units SOD‐PEG −2 x/week‐IP‐ (approximately 11,000 units/gm hemoglobin) ‐ the AD‐SOD group, and Group III was fed AD with 5% SOD rich soybean flour added‐the SF+AD group. The treatments lasted for 5 additional weeks before the animals were sacrificed. Sensitivity to insulin was measured in blood platelets in each group by assaying their glucose uptake following treatment with insulin. Blood plasma and platelets were also assayed for cholesterol and phospholipid. levels. Mean glucose assays of insulin treated platelets from AD‐SOD rabbits measured 8.2 mg/dl of glucose vs 4.5 mg/dl from ADC .platelets‐an 82.2% increase. SF+AD platelets registered a 10.1% increase in insulin sensitivity vs ADC samples. Mean cholesterol levels ( mg/dl ) in blood platelets diminished by 18.8% in the AD‐SOD group and 10.7% in the SF+AD platelets compared to the ADC values. Mean plasma cholesterol levels fell by 16.8% in the AD‐SOD and 19.1% in SF+AD vs ADC plasma. Mean phospholipid levels (mg%) showed a decrease of 12.5% in AD‐SOD platelets and 9.2% in SF+AD platelets vs those in ADC assays. Mean phospholipid levels also fell in AD‐SOD by 17.3% and by 15.8% in SF+AD vs the ADC control values.

Lactobacillus acidophilus CHO-220 and inulin reduced plasma total cholesterol and low-density lipoprotein cholesterol via alteration of lipid transporters

This randomized, double-blind, placebo-controlled, and parallel-designed study was conducted to investigate the effect of a synbiotic product containing Lactobacillus acidophilus CHO-220 and inulin on lipid profiles of hypercholesterolemic men and women. Thirty-two hypercholesterolemic men and women with initial mean plasma cholesterol levels of 5.7±0.32 mmol/L were recruited for the 12-wk study. The subjects were randomly allocated to 2 groups; namely the treatment group (synbiotic product) and the control group (placebo), and each received 4 capsules of synbiotic or placebo daily. Our results showed that the mean body weight, energy, and nutrient intake of the subjects did not differ between the 2 groups over the study period. The supplementation of synbiotic reduced plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol by 7.84 and 9.27%, respectively, compared with the control over 12 wk. Lipoproteins were subsequently subfractionated and characterized. The synbiotic supplementation resulted in a lower concentration of triglycerides in the very low, intermediate, low, and high-density lipoprotein particles compared with the control over 12 wk. The concentration of triglycerides in lipoproteins is positively correlated with an increased risk of atherosclerosis. Our results showed that the synbiotic might exhibit an atheropreventive characteristic. Cholesteryl ester (CE) in the high-density lipoprotein particles of the synbiotic group was also higher compared with the control, indicating greater transport of cholesterol in the form of CE to the liver for hydrolysis. This may have led to the reduced plasma total cholesterol level of the synbiotic group. The supplementation of synbiotic also reduced the concentration of CE in the LDL particles compared with the control, leading to the formation of smaller and denser particles that are more easily removed from blood. This supported the reduced LDL-cholesterol level of the synbiotic group compared with the control. Our present study showed that the synbiotic product improved plasma total- and LDL-cholesterol levels by modifying the interconnected pathways of lipid transporters. In addition, although Lactobacillus acidophilus CHO-220 could deconjugate bile, our results showed a statistically insignificant difference in the levels of conjugated, deconjugated, primary, and secondary bile acids between the synbiotic and control groups over 12 wk, indicating safety from bile-related toxicity.

Melatonin effect on plasma adiponectin, leptin, insulin, glucose, triglycerides and cholesterol in normal and high fat–fed rats

Melatonin effect on body weight progression, mean levels and 24-hr pattern of circulating adiponectin, leptin, insulin, glucose, triglycerides and cholesterol were examined in rats fed a normal or a high-fat diet. In experiment 1, rats fed a normal diet were divided into two groups: receiving melatonin (25 μg/mL drinking water) or vehicle for 9 wk. In experiment 2, animals were divided into three groups: two fed with a high-fat diet (35% fat) and melatonin (25 μg/mL) or vehicle in drinking water for 11 wk, while a third group was given a normal diet (4% fat). At the end of experiments, groups of eight rats were killed at six different time intervals throughout a 24-hr period. Melatonin administration for 9 wk decreased body weight gain from the 3rd wk on without affecting food intake. A significant reduction in circulating insulin, glucose and triglyceride mean levels and disrupted daily patterns of plasma adiponectin, leptin and insulin were observed after melatonin. In high fat-fed rats, melatonin attenuated body weight increase, hyperglycemia and hyperinsulinemia, as well as the increase in mean plasma adiponectin, leptin, triglycerides and cholesterol levels. The high-fat diet disrupted normal 24-hr patterns of circulating adiponectin, insulin and cholesterol, the effects on insulin and cholesterol being counteracted by melatonin. Nocturnal plasma melatonin concentration in control and obese rats receiving melatonin for 11 wk attained values 21-24-fold greater than controls. The results indicate that melatonin counteracts some of the disrupting effects of diet-induced obesity in rats.

Prolonged High-Fat Feeding Enhances Aortic 18F-FDG and 99mTc-Annexin A5 Uptake in Apolipoprotein E-Deficient and Wild-Type C57BL/6J Mice

(18)F-FDG, a marker of the enhanced metabolism characteristic of activated inflammatory cells, and (99m)Tc-annexin A5, a marker of apoptosis, are both widely believed to be useful for the imaging of unstable atheroma (rupture-prone vulnerable plaques [VP]). Serum cholesterol functions as a proinflammatory factor, driving the formation of VP, and affects the immune responses of aortic tissues systemically. It is therefore reasonable to postulate that prolonged cholesterol loading may alter the aortic uptake of these tracers. Here, we evaluated the aortic uptake of (18)F-FDG and (99m)Tc-annexin A5 in apolipoprotein E-deficient (apoE(-/-)) and wild-type mice placed on high-fat diets. Male apoE(-/-) and wild-type (C57BL/6J) mice were maintained on high-fat diets after the age of 5 wk. Wild-type mice fed regular chow were used as controls. At the ages of 10, 18, and 25 wk (5-15 mice per group at each time point), mice were injected with (18)F-FDG or (99m)Tc-annexin A5 after 12 h of fasting. At 1 h after (18)F-FDG injection (or 2 h after (99m)Tc-annexin A5 injection), mice were sacrificed, and the aortas were removed for well-type scintillation counting of radioactivity. The results were expressed as percentage injected dose per gram of tissue and normalized by animal body weight [(ID%/g) x kg]. En face staining was then performed to assess the location and size (surface area) of the lipid pool within each aortic specimen. Concurrent blood samples were obtained to determine the plasma lipid profile of each group. No atherosclerotic lesions were found in wild-type mice regardless of the diet, whereas the lesion area progressively increased with age in apoE(-/-) mice. Mean plasma cholesterol levels remained stable with the regular diet in wild-type mice (73-78 mg/dL) but increased with cholesterol feeding in wild-type mice (143-179 mg/dL) and in apoE(-/-) mice (>1,300 mg/dL). Aortic tracer uptake [(ID%/g) x kg] remained stable with the regular diet in wild-type mice (0.054-0.053 and 0.021-0.023 for (99m)Tc-annexin A5) but increased with cholesterol feeding in wild-type mice (0.164 for (18)F-FDG and 0.036 for (99m)Tc-annexin A5 at 25 wk) and in apoE(-/-) mice (0.249 for (18)F-FDG and 0.047 for (99m)Tc-annexin A5 at 25 wk). The accumulation of (18)F-FDG and (99m)Tc-annexin A5 in aortic tissues is influenced not only by the progression of atherosclerotic disease but also by cholesterol loading over time.

The influence of hepatic lipase C-480T polymorphism on coronary flow reserve in young men is independent of the plasma cholesterol level

Background The hepatic lipase (HL) gene C-480T promoter polymorphism affects gene transcription and enzyme activity and leads to CC, CT, and TT genotypes. Recently, HL expression was detected in macrophages. It has been postulated that HL might have a direct role in the pathogenesis of atherosclerosis without changes in the plasma profile. We hypothesized that the difference of plasma cholesterol level may not influence the effect of HL genotype on coronary reactivity. Methods A total of 108 young men (aged 34 ± 5 years) were genotyped and divided into three groups. These groups contained 45, 49 and 14 men having either normal (4.9 ± 1.2 mmol/L), mildly (5.5 ± 0.8 mmol/L) or severely (7.8 ± 1.9 mmol/L, subjects with familial hypercholesterolemia) elevated mean plasma cholesterol level, respectively. Myocardial blood flow (MBF) was measured at rest and during adenosine or dipyridamole-induced hyperemia with positron emission tomography using [ 15O] H 2O. Results The effect of HL genotype on the indices of MBF was parallel within all cholesterol groups and therefore they were combined. In all subjects, basal flow did not differ between the genotypes. However, men with CC genotype had a significantly higher hyperemic blood flow (3.86 ± 1.26 mL g −1 min −1 versus 3.20 ± 1.38 mL g −1 min −1, p = 0.007), higher coronary flow reserve (CFR, 4.80 ± 1.77 versus 3.77 ± 1.43, p = 0.001) and lower coronary resistance during hyperemia (25.63 ± 9.98 mmHg min g mL −1 versus 35.00 ± 23.95 mmHg min g mL −1, p = 0.003) than T allele carriers. In multivariate regression analysis, after adjustment for age, body mass index, serum lipids, blood pressure, adenosine or dipyridamole administration, and study group, HL polymorphism was an independent predictor of blood flow during hyperemia ( p = 0.016), coronary resistance ( p = 0.014), and CFR ( p = 0.005), respectively. Conclusions The HL C-480T polymorphism is associated with CFR, which is an early indicator of atherosclerosis, independently of the level of plasma cholesterol in young men.

The relationship between lipid profile and erectile dysfunction

The objective of this study is to investigate the relation between serum lipids (cholesterol, LDL, HDL, triglyceride (TG)) and erectile dysfunction (ED). The experimental methods involved comparison of 100 patients with organic ED (mean age of 43.59+/-10.51 y), with 100 healthy individuals (mean age of 43.72+/-9.76 y) regarding their lipid profile from January 2000 to June 2003 (cholesterol, TG, HDL, LDL). The results showed that there was a significant difference between mean plasma cholesterol and LDL levels in the individuals suffering from ED and the control group (P=0.04 and 0.02, respectively). The TG and HDL mean plasma level differences were not significant (P=0.583 and 0.299, respectively). Odds ratios for high plasma cholesterol level (>240 mg/dl) and high plasma LDL level (>160 mg/dl) were 1.74 and 1.97. The R2 was 0.04 for both cholesterol and LDL. Applying linear regression, the coefficient for cholesterol and LDL reduced the International Index of Erectile Function questionnaire scores by -0.036 and -0.035. In conclusion, this study, the correlation of cholesterol and LDL levels with ED strongly supports the role of hyperlipidemia treatment in both the prevention and management of ED.

Effect of a Low-Carbohydrate Diet on Appetite, Blood Glucose Levels, and Insulin Resistance in Obese Patients with Type 2 Diabetes

It is not known how a low-carbohydrate, high-protein, high-fat diet causes weight loss or how it affects blood glucose levels in patients with type 2 diabetes. To determine effects of a strict low-carbohydrate diet on body weight, body water, energy intake and expenditure, glycemic control, insulin sensitivity, and lipid levels in obese patients with type 2 diabetes. Inpatient comparison of 2 diets. General clinical research center of a university hospital. 10 obese patients with type 2 diabetes. Usual diets for 7 days followed by a low-carbohydrate diet for 14 days. Body weight, water, and composition; energy intake and expenditure; diet satisfaction; hemoglobin A1c; insulin sensitivity; 24-hour urinary ketone excretion; and plasma profiles of glucose, insulin, leptin, and ghrelin. On the low-carbohydrate diet, mean energy intake decreased from 3111 kcal/d to 2164 kcal/d. The mean energy deficit of 1027 kcal/d (median, 737 kcal/d) completely accounted for the weight loss of 1.65 kg in 14 days (median, 1.34 kg in 14 days). Mean 24-hour plasma profiles of glucose levels normalized, mean hemoglobin A1c decreased from 7.3% to 6.8%, and insulin sensitivity improved by approximately 75%. Mean plasma triglyceride and cholesterol levels decreased (change, -35% and -10%, respectively). The study was limited by the short duration, small number of participants, and lack of a strict control group. In a small group of obese patients with type 2 diabetes, a low-carbohydrate diet followed for 2 weeks resulted in spontaneous reduction in energy intake to a level appropriate to their height; weight loss that was completely accounted for by reduced caloric intake; much improved 24-hour blood glucose profiles, insulin sensitivity, and hemoglobin A1c; and decreased plasma triglyceride and cholesterol levels. The long-term effects of this diet, however, remain uncertain.

The Relationship between Lipid Profile and Erectile Dysfunction

To evaluate the relationship between serum lipids including cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride and erectile dysfunction (ED). From January 2000 to June 2003, 100 patients with organic ED, who were referred to our center, were selected and their lipid profile (Cholesterol, Triglyceride, HDL, LDL) were assessed. The results were compared with those in 100 healthy individuals. Mean age of men in the study and control groups were 43.72 +/- 9.76 and 43.59 +/- 10.51 years, respectively. Mean plasma cholesterol and LDL levels in individuals suffering from erectile dysfunction were significantly higher than controls (P = 0.04 and P = 0.02, respectively). However, no difference in the mean plasma triglyceride and HDL levels was seen. Odds Ratios for high plasma cholesterol level (>240 mg/dl) and high plasma LDL level (>160 mg/dl) were 1.74 and 1.97, respectively (r2 = 0.04 and r2 = 0.04). Using linear regression analysis, the regression coefficient for cholesterol and LDL versus the International Index of Erectile Dysfunction Questionnaire (IIEF) score were -0.036 and -0.035, respectively (95% confidence interval: 0.98 - 2.5 for cholesterol and 1.13 - 2.81 for LDL). The impact of total cholesterol and particularly LDL on men's erectile function underlines the role of hyperlipidemia treatment in prevention of ED and emerges a holistic management in ED patients.

PREVENTION OF CORONARY HEART DISEASE WITH PRAVASTATIN IN MEN WITH HYPERCHOLESTEROLEMIA

Background Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. Methods We randomly assigned 6595 men, 45 to 64 years of age, with a mean (±SD) plasma cholesterol level of 272±23 mg per deciliter (7.0±0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. Results Pravastatin lowered plasma cholesterol levels by 20 percent and low-density lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death fro...

Fluvastatin enhances the inhibitory effects of a selective angiotensin II type 1 receptor blocker, valsartan, on vascular neointimal formation.

The present studies were undertaken to investigate the potential effect of a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin) to enhance the inhibitory effect of an angiotensin (Ang) II type 1 (AT1) receptor blocker (ARB) on vascular neointimal formation and to explore the cellular mechanism of cross-talk of the AT1 receptor and statin in vascular smooth muscle cells (VSMCs). Neointimal formation and the proliferation of VSMCs induced by cuff placement around the femoral artery were significantly inhibited by treatment with an ARB, valsartan, at a dose of 0.1 mg x kg(-1) x d(-1) and with fluvastatin at a dose of 1 mg x kg(-1) x d(-1), which did not influence mean arterial blood pressure or plasma cholesterol level, whereas valsartan or fluvastatin alone at these doses did not affect neointimal formation or the proliferation of VSMCs. Pretreatment with fluvastatin (approximately 5 micromol/L) for 24 hours significantly inhibited Ang II (1 micromol/L)-mediated DNA synthesis and c-fos promoter activity in cultured VSMCs. Moreover, pretreatment of VSMCs with fluvastatin significantly inhibited Ang II-mediated extracellular signal-regulated kinase (ERK) activation and tyrosine- and serine-phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. AT1 receptor-mediated recruitment of Rac-1 to Janus kinase (Jak) family/STATs was also inhibited by fluvastatin. Consistent with these in vitro results, phosphorylation of ERK, STAT1, and STAT3 was attenuated by the coadministration of valsartan and fluvastatin even at low doses in vivo. These results suggest that the cholesterol-independent inhibition of AT1 receptor-mediated VSMC proliferation by statins may contribute to the beneficial effects of statins combined with an ARB on vascular diseases.

Whole fat rice bran reduces the development of early aortic atherosclerosis in hypercholesterolemic hamsters compared with wheat bran

In this study, Golden Syrian hamsters were fed a nonpurified hypercholesterolemic diet containing 10% coconut oil, 0.05% cholesterol and 20% wheat bran for 2 weeks (HCD) and based on mean plasma cholesterol levels were divided into four groups of 15. Hamsters were then fed the HCD or the HCD containing either 20% de-fatted rice bran (rice fiber), 20% heat-stabilized whole fat rice bran (WFRB), or 20% oat bran in place of wheat bran for 10 weeks. The rice fiber, WFRB, and oat bran diets significantly lowered plasma total cholesterol and very low- and low-density lipoprotein cholesterol levels compared to the wheat bran diet with no reductions in high-density lipoprotein cholesterol. Also, the WFRB diet significantly lowered plasma nonHDL-C levels compared to the rice fiber and oat bran diets. Aortic fatty streak formation was significantly reduced by WFRB diet compared to the wheat bran and rice fiber diets but not the oat bran. This study shows that whole fat rice bran reduces plasma cholesterol levels and the development of early aortic atherosclerosis in hypercholesterolemic hamsters similar to oat bran.

Hypercholesterolemia in Shetland sheepdogs.

Plasma lipoprotein cholesterol in 64 clinically healthy Shetland sheepdogs was evaluated to assess whether the breed is more susceptible to hypercholesterolemia. The incidence of hypercholesterolemia was clearly higher in Shetland sheepdogs and mean plasma cholesterol level was significantly higher in Shetland sheepdogs than in control dogs. Blood biochemical examinations did not evidence the abnormalities, which imply the causative disorders, and thyroid hormone levels were not significantly different from the controls. These results suggest that the cholesterolemia is a primary disorder. Cholesterol fractionation by agarose gel electrophoresis and ultracentrifugation revealed that accumulation of alpha2-migrating lipoproteins was the common characteristic of dogs showing cholesterol level over 250 mg/dl in the breed. Increase in prebeta-beta-lipoproteins was also found in Shetland sheepdogs with marked hypercholesterolemia over 500 mg/dl. Therefore. Shetland sheepdogs may include more dogs with primary disorders in lipoprotein metabolism, which cause hypercholesterolemia. at least in Japan.

Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E.

Apo E is a key molecule in the lipoprotein metabolism; thus, genetic manipulation of apo E may prove useful in the treatment of hypercholesterolemia. To test the feasibility of this idea, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpress the rat apo E transgene (ETg+/+:LDLRKO), and compared their plasma lipoprotein profiles with those of nonexpressing LDLR knockout mice (ETg-/-:LDLRKO). On a normal chow diet, the mean plasma cholesterol level of ETg+/+:LDLRKO mice was significantly lower than that of ETg-/-:LDLRKO mice (189 versus 240 mg/dl, P < 0. 01). The LDL fraction was selectively reduced in the ETg+/+:LDLRKO mice. Despite the challenge with an atherogenic diet, cholesterol lowering was persistently observed and fatty streak lesions in the aortic sinus were significantly suppressed in the mice overexpressing apo E. These results imply that stimulation of hepatic production of apo E may be used as a promising adjunctive therapy for homozygous familial hypercholesterolemia.

Liver-directed gene transfer and prolonged expression of three major human ApoE isoforms in ApoE-deficient mice.

Apolipoprotein E (apoE) plays a key role in lipoprotein metabolism and may have other important biological functions. In humans, there are three common, naturally occurring isoforms of apoE that are associated with differences in lipid levels and atherosclerosis. However, the direct in vivo effects of the apoE isoforms on lipoprotein metabolism and atherosclerosis are not yet fully understood. To investigate the effect of the apoE isoforms in vivo, we constructed second-generation recombinant adenoviruses encoding each of the apoE isoforms. These recombinant adenoviruses were injected intravenously into apoE-deficient mice fed a Western diet (mean baseline cholesterol level 1401 mg/dl) in order to study their effects in the absence of endogenous mouse apoE. Hepatic expression of apoE3 and apoE4 completely normalized the lipoprotein profile; 3 d after injection, mean plasma cholesterol levels were 194 and 217 mg/ dl, respectively, and this effect was maintained for at least 6 wk. Expression of apoE2 had much less effect on lipoprotein levels (mean cholesterol level 752 mg/dl 3 d after injection), despite much higher plasma levels of apoE2 compared with apoE3 and apoE4; by 6 wk after injection the cholesterol levels had returned to baseline levels in the apoE2-expressing mice. Expression of all three isoforms significantly increased HDL cholesterol levels by approximately threefold and was independent of the cholesterol-lowering effect. ApoE transgene expression was substantially prolonged compared with that achieved using a first generation adenovirus and apoE was readily detected in plasma 3 mo after virus injection. These studies demonstrate: (a) prolonged in vivo expression of human apoE isoforms in apoE deficient mice after second-generation recombinant adenovirus-mediated somatic gene transfer; and (b) significantly impaired ability of apoE2 in vivo to mediate clearance of remnant lipoproteins in apoE-deficient mice fed a Western diet compared with apoE3 and apoE4.

リポ蛋白代謝変異マウスモデルにおける動脈硬化の比較

Murine models of atherosclerosis is increasingly used for the studies of atherosclerosis. 1) We compared atherosclerosis of LDLR-/-, apo E-/-or LDLR-/-;apo E-/- mice in light of their lipoprotein profiles. The mice were fed a nomlal chow, and sacrified at age 12 months. Aortic lesions were visualized by staining with Sudan IV. Wild type mice had no lesins. The lesions of the LDLR-/- mice were restricted to the aortic arch, couprising only 5% of the total surface area of the aorta. On the other hand, the lesions of the apo E-/- mice were more extensive and involved 30% of the total surface area. The aortic arches were totally diseased with skipping lesions in other parts of the aorta. Lesions in the LDLR-/-;apo E-/- mice deVeloped advanced further. Most of he luminal surface of he aorta (80%) was covered with lesion coalescence. Mean plasma cholesterol levels of the wild type, LDLR-/-, apo E-/-, and LDLR-/-;apo E-/- mice were 101, 388, 543, and 578mg/dl, respectively. Thus, the differences in atherosclerotic progression between apo E-/- and LDLR-/-;apo E-/- mice were not attributable to the differences in plasua cholesterol levels but to a coubined elevation of LDL and reunants. In conclusion, LDL accelerates atherosclerosis synergis. tically with reunant lipoproteins. LDLR-/-;apo E-/- mice may serve as a model of rampant atherosclerosis. 2) Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Conflicting results have been reported concerning its role in atherogenesis. To determine the effects of the overexpressed LPL on diet-induced atherosclerosis, we have generated low density lipoprotein receptor (LDLR) knockout mice which overexpressed huuan LPL transgene (LPL/LDLRKO) and compared their plasma lipoproteins and atherosclerosis with those in non-expressing LDLR-knockout mice (LDLRKO). On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 vs 236mg/dl) andmodest decrease in mean cholesterol levels (300 vs 386mg/dl) as compared with LDLRKO mice. Larger lipoprotein particles of LDL/LDL were selectively reduced in LPL/LDLRKO mice. On an atherogenic diet, both mice exhibited severe hypercholesterolemia. But, mean plasua cholesterol levels in LPL/LDLRKO mice were still suppressed as coupared with that in LDLRKO mice (1, 357 vs 2, 187mg/dl). Marked reduction in a larger subfraction of IDL/LDL, which conceivably corresponds to remnant lipoproteins, was observed in the LPL/LDLRKO mice. LDLKO mice developed severe fatty streak lesions in the aortic sinus after feeding with the atherogenic diet for 8 weeks. In contrast, mean lesion area in the LPL/LDLRKO uice was 18-fold smaller than than that in LDLRKO mice. We suggest that the altered lipoprotein profile, in particular, reduced level of remnant lipoproteins is mainly responsible for the protection by LPL against atherosclerosis.