High Plasma Cholesterol Levels Research Articles

Visceral adipose tissue accumulation, secretory phospholipase A2-IIA and atherogenecity of LDL

The aim of the present study was to investigate the combined impact of visceral adipose tissue (VAT) and secretory group IIA phospholipase A(2) (sPLA(2)-IIA) concentrations on the atherogenicity of low-density lipoprotein (LDL) particles among men. Analyses were conducted in 74 mid-obese healthy men (age: (mean+/-s.d.) 37.9+/-11.7 years). Plasma levels of sPLA(2)-IIA were measured with a commercial ELISA and VAT levels were assessed by computed tomography. Distinct subpopulations of LDL particles were characterized from whole plasma using nondenaturating 2-16% gradient gel electrophoresis. Data indicated that plasma sPLA(2)-IIA levels were approximately 29% (P=0.007) higher among men characterized by a higher accumulation of VAT (>142 vs < or =142 cm(2)). Men having high plasma sPLA(2)-IIA levels (> or =127.2 ng/dl, the median value), were characterized by higher levels of plasma cholesterol (C) and apolipoprotein (apo) B, LDL-C, LDL-apoB, oxidized LDL (OxLDL) and by smaller LDL particles compared to men with sPLA(2)-IIA<127.2 ng/dl. Multiple regression analyses showed that plasma triglycerides and sPLA(2)-IIA levels explained 22.7 and 11.8% of the variance in LDL peak particle size, respectively. Levels of VAT and of sPLA(2)-IIA were the strongest correlates of OxLDL levels explaining, respectively, 15.0 and 5.5% of their variability. Both VAT and sPLA(2)-IIA levels modulate the atherogenecity of LDL by accounting for the reduction in their size and their susceptibility to oxidation.

PROGRESSION OF SEVERE ATHEROSCLEROSIS AND INCREASED ARTERIAL PULSE PRESSURE IN THE NEWLY DEVELOPED HERITABLE MIXED HYPERLIPIDAEMIC RABBITS

We have recently segregated a new line of rabbit, named TGH, with severely high levels of plasma triglyceride and cholesterol. The aim of the present study was to investigate the progression of atherosclerosis and haemodynamic parameters in TGH rabbits. 2. Japanese white (JW) and TGH rabbits (24-27 months old) were anaesthetized with ketamine and xylazine. Plasma concentrations of triglyceride were 63.1 8.0 and 446.0 35.2 mg/dL in JW and TGH rabbits, respectively. Blood pressure was measured by a catheter implanted in the femoral artery. Histological examinations were performed using haematoxylin-eosin and elastica-Masson trichrome staining to detect atherosclerotic lesions. 3. The JW rabbits had no atherosclerotic lesions. In TGH rabbits, severe atherosclerotic lesions were observed throughout the aorta, especially in the aortic arch. Basal femoral arterial pressure was not significantly different between JW and TGH rabbits. However, the basal pulse pressure in TGH rabbits (48.3 4.5 mmHg) was significantly greater than that of JW rabbits (28.0 5.6 mmHg). Intravenous infusion of N(G)-nitro-L-arginine methyl ester (L-NAME; 26.9 mg/kg) increased the blood pressure of TGH and JW rabbits. There was no significant difference in the response to L-NAME between the two rabbit strains. 4. The present study shows that severe atherosclerotic changes develop in TGH rabbits and suggests that the hyperlipidaemia combined with hypercholesterolaemia and hypertriglyceridaemia is an important factor for promoting atherosclerosis in TGH rabbits. The greater pulse pressure in TGH rabbits may be due to the increased vascular stiffness with atherosclerosis. 5. This newly developed TGH rabbit line of heritable hypertriglyceridaemia with hypercholesterolaemia will become a useful animal model for studies on the role of hyperlipidaemia in the progression of atherosclerosis and in many atherosclerosis-related diseases.

We-P13:347 Lower waist circumference threshold for metabolic syndrome in a Malay Asian population

Physiological levels of wild-type (wt) apolipoprotein E (apoE) in plasma mediate the clearance of cholesterol-rich atherogenic lipoprotein remnants while higher than normal plasma apoE concentrations fail to do so and trigger hypertriglyceridemia. This property of wt apoE reduces significantly its therapeutic value as a lead biological for the treatment of dyslipidemia. Recently, we reported the generation of a recombinant apoE variant, apoE4 [L261A, W264A, F265A, L268A, V269A] (apoE4mut1) with improved biological functions. Specifically, in apoE-deficient (apoE−/−) mice this variant can normalize high plasma cholesterol levels without triggering hypertriglyceridemia, even at supraphysiological levels of expression. In the present study we performed pharmacodynamic and pharmacokinetic analysis of apoE4mut1 in experimental mice. Using adenovirus-mediated gene transfer in LDL receptor deficient (LDLr−/−) mice, we show that the cholesterol lowering potential of apoE4mut1 is dependent on the expression of a functional classical LDLr. Bolus infusion of apoE4mut1-containing proteoliposomes in apoE−/− mice fed western-type diet for 6 weeks indicated that exogenously synthesized apoE4mut1 maintains intact its ability to normalize the high cholesterol levels of these mice with a maximum pharmacological effect obtained at 10 h post-treatment. Interestingly, plasma cholesterol levels remained significantly reduced up to 24 h following intravenous administration of apoE4mut1 proteoliposomes. Measurements of plasma apoE levels indicated that apoE4mut1 in the form of proteoliposomes used in the study has a half-life of 15.8 h. Our data suggest that purified apoE4mut1 may be an attractive new candidate for the acute correction of hypercholesterolemia in subjects expressing functional LDL receptor.

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.

Dietary consumption of green tea catechins attenuate hyperlipidaemia-induced atherosclerosis and systemic organ damage in mice

Objective — The effects of consuming green tea catechins on the development of hyperlipidaemiainduced systemic organ damage have not been well studied; we investigated the effect using low density lipoprotein receptor knockout mice.Methods and Results — Mice were treated with high cholesterol food containing 0.2 or 4% catechins and they were supplemented for 35 weeks. High plasma cholesterol levels, liver and renal dysfunctions were observed in no catechin fed mice, while chow containing catechin suppressed these levels and damages. Severe atherosclerosis of the aorta, fatty liver and renal injury were also shown in the control mice; inflammatory factors were enhanced in these lesions of nontreated mice.The lesions were attenuated with suppression of the inflammatory factors in the chow-contained catechin treatment group.Conclusion — Dietary consumption of tea catechins attenuated the development of the systemic organ damage; thus, this has a clinical effect against systemic inflammatory diseases.

Naturally Derived Micelles for Rapid in Vitro Screening of Potential Cholesterol-Lowering Bioactives

A high plasma cholesterol level, especially low-density lipoprotein cholesterol, indicates increased risk of cardiovascular diseases. Plasma cholesterol levels are influenced by diet and cholesterol biosynthesis, uptake, and secretion. Cholesterol uptake involves solubilization into complex phospholipid spherical bodies termed micelles that facilitate the transport of lipids through the gut brush border membrane into enterocytes. In vitro assays reported to date to determine potential cholesterol-lowering effects of various compounds require artificial micelle preparations that are elaborate and time-consuming to prepare. The aims of this study were to compare the efficacy of artificially prepared micelles with naturally derived micelles from pig's bile and to test their ability to assess potential inhibitors of cholesterol uptake. The suitability of pig's bile-derived micelles was tested both at the level of the micelle and at cellular uptake using cultured Caco-2 cells. Known cholesterol uptake inhibitors at the micelle (green tea catechins) and at the Caco-2 cell (beta-lactoglobulin-derived peptide, IIAEK) were used as reference inhibitory compounds. It was concluded that pig's bile was a rapid, reproducible, convenient, and cost-effective source of micelles for cholesterol micelle solubility and cellular uptake assay systems and is suitable for screening purposes focused on identifying potential cholesterol-lowering agents.

Influence of personality traits on plasma levels of cortisol and cholesterol

The literature reports many organic malfunctions that are associated with elevated plasma cortisol and cholesterol levels. The present investigation was concerned with the influence of personality on plasma levels of cortisol and cholesterol. To that effect these variables were determined in a group of 20 subjects who answered the Big-Five Inventory. for measurements of personality traits. It was found that: among the 5 personality traits, extraversion was positively correlated to plasma levels of cortisol and cholesterol while the correlation was negative for neuroticism. The positive correlation between extraversion and plasma cortisol and cholesterol, as well as with the responses to stress as shown in a previous study, are similar to findings previously reported on type A individuals. Further studies are needed with a larger group of subjects to conclude to a direct causal relationship between extraversion and the high levels of plasma cortisol and cholesterol, or a predisposition to some organic malfunctions as is the case for type A.

Examining the interaction of apo E and neurotoxicity on a murine model of ALS-PDC

Epidemiological studies have shown a positive relationship between cycad flour consumption and the development of the neurodegenerative disorder, amyotrophic lateral sclerosis - parkinsonism - dementia complex (ALS-PDC). Apolipoprotein E (apo E) allele variations have been associated with genetic susceptibility in neurodegenerative diseases, including ALS-PDC. We have studied cycad toxicity in a mouse model of ALS-PDC with a particular interest in its impact on the central nervous system (CNS) in both apo E knock-out (KO) mice and their wild-type (WT) counterparts. Behavioral motor tests, motor neuron counts, and immunohistochemical staining in brain and spinal cord, as well as routine histological examinations on internal organs, were performed to evaluate cycad toxicity. Plasma cholesterol levels were also measured before and during the study. Cycad treatment was associated with higher levels of plasma cholesterol only in apo E KO mice; increased levels of plasma cholesterol did not result in increased athero genesis. Cycad-fed wild-type mice developed progressive behavioral deficits including ALS-PDC-like pathological outcomes, while cycad-fed apo E KO mice were not significantly affected. Cycad-fed wild-type mice had shorter gait length measurements along with higher active caspase-3 levels in the striatum, substantia nigra, primary motor cortex, and spinal cord as compared with corresponding controls. These changes were associated with decreased labeling for glutamate transporter 1B and tyrosine hydroxylase activity levels. No evidence of cycad toxicity was observed in internal organs of either wild-type or apo E KO mice. Our data demonstrate that apo E KO mice are less susceptible to cycad toxicity, suggesting a role for apo E as a possible genetic susceptibility factor for some forms of toxin-induced neurodegeneration.

Increased Bone Formation in Mice Lacking Apolipoprotein E

ApoE is a plasma protein that plays a major role in lipoprotein metabolism. Here we describe that ApoE expression is strongly induced on mineralization of primary osteoblast cultures. ApoE-deficient mice display an increased bone formation rate compared with wildtype controls, thereby showing that ApoE has a physiologic function in bone remodeling. Apolipoprotein E (ApoE) is a protein component of lipoproteins and facilitates their clearance from the circulation. This is confirmed by the phenotype of ApoE-deficient mice that have high plasma cholesterol levels and spontaneously develop atherosclerotic lesions. The bone phenotype of these mice has not been analyzed to date, although an association between certain ApoE alleles and BMD has been reported. Primary osteoblasts were isolated from newborn mouse calvariae and mineralized ex vivo. A genome-wide expression analysis was performed during the course of differentiation using the Affymetrix gene chip system. Bones from ApoE-deficient mice and wildtype controls were analyzed using radiography, micro CT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring urinary collagen degradation products. Lipoprotein uptake assays were performed with (125)I-labeled triglyceride-rich lipoprotein-remnants (TRL-R) using primary osteoblasts from wildtype and ApoE-deficient mice. Serum concentrations of osteocalcin were determined by radioimmunoassay after hydroxyapatite chromatography. ApoE expression is strongly induced on mineralization of primary osteoblast cultures ex vivo. Mice lacking ApoE display a high bone mass phenotype that is caused by an increased bone formation rate, whereas bone resorption is not affected. This phenotype may be explained by a decreased uptake of triglyceride-rich lipoproteins by osteoblasts, resulting in elevated levels of undercarboxylated osteocalcin in the serum of ApoE-deficient mice. The specific induction of ApoE gene expression during osteoblast differentiation along with the increased bone formation rate observed in ApoE-deficient mice shows that ApoE has a physiologic role as a regulator of osteoblast function.

Plasma Plant Sterol Levels

The disorder Phytoterolemia is characterized by ≈50-fold elevations in plasma plant sterol levels as well as tendon xanthomas and premature coronary heart disease.1 On pathological examination the xanthomas and arteries of these patients contain plant sterols.2 This has raised questions of whether plant sterols are proatherogenic and whether the “normal” variation of plasma plant sterol levels in the general population is a risk factor for coronary heart disease. The article by Wilund et al in the December 2004 issue of Arteriosclerosis, Thrombosis, and Vascular Biology attempts to answer both questions through a mouse atherosclerosis study and an epidemiological study.3 See December 2004, page 2326 Phytosterolemia is an autosomal recessive disease, which results from mutations in one or both of two adjacent genes, ABCG5 and ABCG8 .4,5 These genes encode hemi transporters that regulate plasma plant sterol levels by limiting intestinal plant sterol absorption and promoting biliary plant sterol excretion. It is not entirely clear that the elevated plant sterols in Phytosterolemics account for their premature coronary heart disease, because some patients also have very high plasma cholesterol levels in early childhood and most adults with the disorder have moderately elevated plasma cholesterol levels. Therefore, it could be the associated hypercholesterolemia, rather than the elevated plasma plant sterol levels, that is responsible for the premature coronary heart disease. Plasma plant sterols cannot be synthesized endogenously and are completely derived from the diet. In Western populations, the major plasma plant sterols are campesterol (≈0.33 mg/dL) and sitosterol (≈0.25 mg/dL), with all others, including stigmasterol and brassicasterol, present at much lower concentrations. In the …

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.

EFFECT OF A SOYBEAN PRODUCT ON SERUM LIPID LEVELS IN FEMALE UNIVERSITY STUDENTS

1. A dietary intervention study targeting female students by using cake containing soybean protein and isoflavone was conducted. Female students (n = 120) were divided into three Groups (A, 6.26 g of soybean protein and isoflavone at 50 mg/day; B, 1.36 g soybean protein and isoflavone 50 mg; and C, a wheat puff as placebo). Intervention period was 4 weeks. The ratio of hypercholesterol in each group indicated a high value; A: 25%, B: 17.9% and C: 24.4%. 2. Total cholesterol as well as the rate of hypercholesterolemia decreased in Group A. The average total cholesterol significantly reduced (P < 0.001) from 242 +/- 17 to 220 +/- 25 mg/dL in Group A. 3. Dietary intake of soy protein for 4 weeks could be effective in reducing CHD risk among Japanese female students with a high plasma cholesterol level.

Vascular Inflammation in Aging

Although epidemiologic studies have revealed that high plasma cholesterol or high homocysteine levels, as well as diabetes, hypertension and smoking are important risk factors for atherosclerotic vascular disease, the deleterious effects of these conditions can be delayed or significantly attenuated by therapeutic interventions. Since the population in the Western world is aging, advancing age itself became one of the most significant risk factors for the development of atherosclerosis. Atherosclerosis is a chronic inflammatory disease, however, the mechanisms by which advanced age per se promotes vascular inflammation are not well understood. In the present review the authors propose a model for age-related alterations in cytokine expression, increased oxidative stress and decreased bioavailability of NO that underlie a pro-inflammatory phenotype of aged vessels promoting the development of atherosclerosis in the elderly.

Role of vasa vasorum in transendothelial solute transport in the coronary vessel wall: a study with cryostatic micro-CT.

Using cryostatic microscopic computed tomography (micro-CT), we sought to determine the role of coronary vasa vasorum (VV) in transendothelial solute transport in arteries with normal and increased permeability due to high plasma cholesterol levels. In 6-mo-old pigs on a normal (n=23) and 2% high cholesterol (HC) diet (n=8), 2-cm segments of the proximal left anterior descending coronary arteries were removed in vivo after a selective injection of X-ray contrast solution. Harvesting of the specimens occurred at 0, 15, 25, 35, or 45 s after completion of the contrast injection. Specimens were snap frozen and scanned in our cryostatic micro-CT. The spatial distribution of contrast in the coronary artery wall was quantified using the CT images. Right coronary arteries were infused with Microfil to determine VV density (VV/mm2) and the cumulative lumen surface area (mm2/mm3). Transendothelial diffusion of contrast into the coronary vessel wall is a dynamic process starting at both the subintima and the adventitia. The subintimal opacification moves as a wave toward the adventitia, whereas the adventitial wave resolves. The coronary vessel wall in animals on a HC diet shows higher opacification than in normal coronary arteries without an increase of VV total luminal surface area. The loss of endothelial integrity in hypercholesterolemia significantly alters VV solute washin to, and washout from, the coronary artery wall.

Update on statins

High plasma cholesterol levels lead to the formation of atheromatous plaques in blood vessels, and this can ultimately lead to obstruction or occlusion of the vessel. Cholesterol is transported in the blood as lipoproteins, which can be either low density or high density. Atherogenesis is correlated to high levels of low density lipoprotein (LDL), while high density lipoprotein (HDL) is involved in clearing cholesterol away from the arteries and a high HDL is associated with a lower risk of cardiovascular disease. In 2000, the Government published the National Service Framework (NSF) for Coronary Heart Disease. The aim of the NSF is to improve the standard of care to those patients with existing or at high risk of developing coronary heart disease. One of the target areas is lowering cholesterol concentrations. There are a large proportion of patients who would benefit from statin therapy who are not currently receiving treatment, and a large number of patients on statins who are not being adequately treated. Treating all eligible patients will have a huge impact on prescribing costs to the NHS. The standards set down in the NSF advocate the use of statins and dietary advice in: ● Patients with diagnosed coronary heart disease or other occlusive arterial disease (secondary prevention). ● Patients without diagnosed coronary heart disease or other occlusive arterial disease but with a coronary heart disease event risk greater than 30% over 10 years (primary prevention).

Feeding dairy cows with soybean by-products: effects on metabolic profile

Soybean by-products are currently used in Rio Grande do Sul, Brazil, as a source of protein in dairy cows. However, the high protein breakdown of this feed source in the rumen causes loss of the intrinsic quality of the protein and increases plasma urea with deleterious consequences to animal metabolism. Thermal treatment of soybean can overcome this limitation. The aim of this study was to evaluate the metabolism of dairy cows fed with thermally treated soybean and raw soybean, through the analyses of the metabolic profile of plasma and milk. Twelve Holstein cows in mid-lactation period were studied using four treatments: commercial concentrated of protein, soybean meal, raw soybean and roasted soybean. Protein and urea levels in milk were measured in morning and afternoon samples. Data were arranged in a Latin square design (4 treatments and 3 animals in each square). There were no significant differences in glucose, beta-hydroxybutyrate, calcium, phosphorus and magnesium concentrations among treatments. Cows consuming raw and thermally treated soybean had higher levels of plasma cholesterol. Cows consuming roasted soybean had lower level of plasma and milk urea in the morning. Afternoon milk samples had higher levels of urea than morning samples. It is suggested that thermally treated soybean was effective in diminishing the breakdown of protein in the rumen. It is better to employ morning milk samples to evaluate metabolic profile than afternoon samples.

Update on statins.

High plasma cholesterol levels lead to the formation of atheromatous plaques in blood vessels, and this can ultimately lead to obstruction or occlusion of the vessel. Cholesterol is transported in the blood as lipoproteins, which can be either low density or high density. Atherogenesis is correlated to high levels of low density lipoprotein (LDL), while high density lipoprotein (HDL) is involved in clearing cholesterol away from the arteries and a high HDL is associated with a lower risk of cardiovascular disease. In 2000, the Government published the National Service Framework (NSF) for Coronary Heart Disease. The aim of the NSF is to improve the standard of care to those patients with existing or at high risk of developing coronary heart disease. One of the target areas is lowering cholesterol concentrations. There are a large proportion of patients who would benefit from statin therapy who are not currently receiving treatment, and a large number of patients on statins who are not being adequately treated. Treating all eligible patients will have a huge impact on prescribing costs to the NHS. The standards set down in the NSF advocate the use of statins and dietary advice in: ● Patients with diagnosed coronary heart disease or other occlusive arterial disease (secondary prevention). ● Patients without diagnosed coronary heart disease or other occlusive arterial disease but with a coronary heart disease event risk greater than 30% over 10 years (primary prevention).

Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene

We describe a Sicilian family presenting a recessive form of hypercholesterolemia harboring a mutation of the autosomal recessive hypercholesterolemia (ARH) gene. In two of the three sibs, a 26-year-old male and a 22-year-old female, a severe hypercholesterolemia was diagnosed with very high levels of plasma cholesterol (15.9 and 12.2 mmol/l, respectively); tendon xanthomatas and xanthelasms were present and in the male proband was documented a diffuse coronary atherosclerotic disease with a rapid and fatal progression. Both the parents had normal or slightly increased levels of plasma cholesterol. All causes of secondary hypercholesterolemia were ruled out as well as an involvement of the LDL receptor or apoB genes. β-Sitosterol plasma levels were in the normal range. Cultured fibroblasts from skin biopsy from parents and the two probands displayed a normal ability to bind and degrade 125I-LDL. Direct sequencing of ARH gene demonstrated the presence of a 432insA mutation in homozygosis in the two probands; parents were heterozygotes for the same mutation. This mutation is the first report of a mutation of the ARH gene responsible for recessive forms of hypercholesterolemia in Sicily.

Comparison of the effects of α-tocopherol, ubiquinone-10 and probucol at therapeutic doses on atherosclerosis in WHHL rabbits

Oxidative modification of lipoproteins may trigger and maintain atherogenesis. We compared the effects of different antioxidants (α-tocopherol, probucol, ubiquinone-10) at doses similar to those used in humans in Watanabe Heritable Hyperlipidemic (WHHL) rabbits for 12 months. Aortic lesions were analyzed for their extent and cellular composition of lesions, mean thickness of fibrous caps and density of smooth muscle cells therein, content of antioxidants, non-oxidized and oxidized lipids. Compared to controls, probucol significantly lowered the extent and macrophage content of lesions and increased the existence and smooth muscle cell density of fibrous caps. α-Tocopherol supplementation increased the aortic content of vitamin E, but had no decreasing effect on either the accumulation of macrophage-specific antigen in the aorta or lesion size. Nevertheless, both probucol and α-tocopherol significantly decreased in vitro LDL oxidizability, measured under typically strong oxidative conditions. Ubiquinone-10 supplement increased lesion size and the fraction of lesions containing fibrous caps; however, LDL oxidizability remained unaffected by ubiquinone-10 treatment. None of the antioxidants tested lowered oxidized lipids within aortic tissue; however, long-term treatment with probucol provided the most effective anti-atherosclerotic effect, while α-tocopherol may be pro-atherogenic and ubiquinone-10 exerts ambivalent effects. Our data suggest that (i) widely used oxidation measures, such as ex-vivo LDL oxidizability, do not reflect the degree of atherosclerosis; and (ii) long-term beneficial effects of relatively low doses of antioxidants may be outweighed by high levels of plasma cholesterol in WHHL rabbits.

ApoE Deficiency Compromises the Blood Brain Barrier Especially After Injury

Apolipoprotein E (apoE) mediates lipoprotein uptake by receptors such as the LDL receptor (LDLR). The isoform apoE4 has been linked to Alzheimer's disease and to poor outcomes after brain injury. Astrocytes that induce blood brain barrier (BBB) properties in endothelium also produce apoE. We decided to investigate the role of apoE in BBB function and in the restoration of BBB after brain injury. Wild-type (WT) mice and mice deficient in apoE or LDLR were fed normal chow or diets rich in fat and cholesterol. The BBB leakage was determined through injection of Evans blue dye and measurement of the amount of dye extravasated in the brains 3 hours later. Brain injury was induced by applying dry ice directly onto the excised parietal region of the brain. The mice were given 7 days to recover. In some experiments, peroxidase was infused to observe the site of leakage by histology. We found 70% more spontaneous leakage of injected Evans blue dye in the brains of apoE-/- mice than in wild type. This increase in permeability appeared selective for the brain. The leaky BBB in apoE-/- mice may provide an explanation for the neurological deficits seen in these animals. In an established model of BBB leakage induced by trauma (cold injury), the apoE-/- mice showed even more compromised BBB function, compared with WT mice, suggesting that apoE is important for BBB recovery. No deficit in BBB was observed in injured LDLR-/- mice, even on Western Diet. In contrast, higher plasma cholesterol levels in apoE-/- mice further increased BBB leakage after injury. We extracted 5x more Evans blue from these brains than from WT. In the injury model, injection of peroxidase resulted in prominent retention of this protein in the cortex of apoE-/- but not in WT. Our results show that the combination of loss of apoE function with high plasma cholesterol and especially brain injury results in dramatic BBB defects in the cortex and may explain in part the importance of apoE in Alzheimer's disease and in successful recovery from brain injury.