Circulating oxidized LDL is associated with the occurrence of echolucent plaques in the carotid artery in 61-year-old men.

OBJECTIVE The aim of this study was to elucidate the relationship between the echogenicity of carotid artery plaques and the following risk factors: circulating oxLDL, hsCRP, the metabolic syndrome (MetS), and several of the traditional cardiovascular (CV) risk factors. MATERIAL AND METHODS A cross-sectional population-based study of 513 sixty-one-year-old men. The levels of circulating oxLDL were determined in plasma samples by sandwich ELISA utilizing a specific murine monoclonal antibody (mAb-4E6). High-sensitivity CRP was measured in plasma by ELISA. Plaque occurrence, size and echogenicity were evaluated from B-mode ultrasound registrations in the carotid arteries. Plaque echogenicity was assessed based on a four-graded classification scale. RESULTS A higher frequency of echolucent carotid plaques was observed with increasing levels of oxLDL and systolic blood pressure (p = 0.008 and p = 0.041, respectively). Subjects with the MetS had a significantly higher frequency of echogenic plaques than subjects without the MetS (p = 0.009). In a multiple logistic regression analysis, oxLDL turned out to be independently associated with echolucent carotid plaques. CONCLUSIONS The occurrence of echolucent carotid plaques was associated with oxLDL and systolic blood pressure, and oxLDL was associated with echolucent carotid plaques independently of systolic blood pressure.

JTT-130, a Microsomal Triglyceride Transfer Protein (MTP) Inhibitor Lowers Plasma Triglycerides and LDL Cholesterol Concentrations without Increasing Hepatic Triglycerides in Guinea Pigs

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.

Plasma LDL and HDL Characteristics and Carotenoid Content Are Positively Influenced by Egg Consumption in an Elderly Population

BACKGROUND : Approximately 1/3 of individuals have a high plasma response to dietary cholesterol (hyper-responders). Although increases in both LDL and HDL cholesterol have been observed, limited data exist regarding effects of egg consumption on lipoprotein subclasses and circulating carotenoids. METHODS : 29 postmenopausal women (50-68 y) and 13 men (60-80 y) were assigned to either 3 eggs (EGG, 640 mg cholesterol/d) or an equal volume of cholesterol-free egg substitute (SUB, 0 mg cholesterol/d) for 30 d. Following a 3 wk wash out, subjects crossed over to the alternate diet. Individuals with a response to dietary cholesterol > 2.2 mg/dL for each additional 100 mg of dietary cholesterol were classified as hyper-responders while hypo-responders were those with a response /= 21.2 nm) less atherogenic LDL particle (P < 0.001) and larger HDL particle (> 8.8 nm) (P < 0.01), with no significant difference in the total number of LDL or HDL particles. Regardless of response classification, all individuals had an increase in plasma lutein (from 32.4 +/- 15.2 to 46.4 +/- 23.3 ng/L) and zeaxanthin (from 8.8 +/- 4.8 to 10.7 +/- 5.8 ng/L) during EGG, yet hyper-responders displayed higher concentrations of carotenoids when compared to hypo-responders CONCLUSION : These findings suggest that the increases in LDL-C and HDL-C due to increased egg consumption in hyper-responders are not related to an increased number of LDL or HDL particles but, to an increase in the less atherogenic lipoprotein subfractions. Also, increases in plasma carotenoids after EGG may provide a valuable dietary source for this population.

Empfehlenswerthe Orchideen zur Schnittblumen-Produktion : Coelogyne cristata Ldl.

von R. Brandt

Lycaste lanipes Ldl.

Von M. Hellwig

Genome-wide association study of LDL-cholesterol over ApoB ratio

Genome-Wide Association Study analytical (GWAS) methods were applied in a large biracial sample of individuals to investigate variation across the genome for its association with a surrogate low-density lipoprotein (LDL) particle size phenotype, the ratio of LDL-cholesterol level over ApoB level. Genotyping was performed on the Affymetrix 6.0 GeneChip with approximately one million single nucleotide polymorphisms (SNPs). The ratio of LDL cholesterol to ApoB was calculated, and association tests used multivariable linear regression analysis with an additive genetic model after adjustment for the covariates sex, age and BMI. Association tests were performed separately in African Americans and Caucasians. There were 9,562 qualified individuals in the Caucasian group and 3,015 qualified individuals in the African American group. Overall, in Caucasians two statistically significant loci were identified as being associated with the ratio of LDL-cholesterol over ApoB: rs10488699 (p<5 x10-8, 11q23.3 near BUD13) and the SNP rs964184 (p<5 x10-8 11q23.3 near ZNF259). We also found rs12286037 ((p<4x10-7) (11q23.3) near APOA5/A4/C3/A1 with suggestive associate in the Caucasian sample. In exploratory analyses, a difference in the pattern of association between individuals taking and not taking LDL-cholesterol lowering medications was observed. Individuals who were not taking medications had smaller p-value than those taking medication. In the African-American group, there were no significant (p<5x10-8) or suggestive associations (p<4x10-7) with the ratio of LDL-cholesterol over ApoB after adjusting for age, BMI, and sex and comparing individuals with and without LDL-cholesterol lowering medication. Conclusions: There were significant and suggestive associations between SNP genotype and the ratio of LDL-cholesterol to ApoB in Caucasians, but these associations may be modified by medication treatment.^

Direct Binding of Occupied Urokinase Receptor (uPAR) to LDL Receptor-related Protein Is Required for Endocytosis of uPAR and Regulation of Cell Surface Urokinase Activity

Low-density lipoprotein receptor-related protein (LRP) mediates internalization of urokinase:plasminogen activator inhibitor complexes (uPA:PAI-1) and the urokinase receptor (uPAR). Here we investigated whether direct interaction between uPAR, a glycosyl-phosphatidylinositol–anchored protein, and LRP, a transmembrane receptor, is required for clearance of uPA:PAI-1, regeneration of unoccupied uPAR, activation of plasminogen, and the ability of HT1080 cells to invade extracellular matrix. We found that in the absence of uPA:PAI-1, uPAR is randomly distributed along the plasma membrane, whereas uPA:PAI-1 promotes formation of uPAR-LRP complexes and initiates redistribution of occupied uPAR to clathrin-coated pits. uPAR-LRP complexes are endocytosed via clathrin-coated vesicles and traffic together to early endosomes (EE) because they can be coimmunoprecipitated from immunoisolated EE, and internalization is blocked by depletion of intracellular K+. Direct binding of domain 3 (D3) of uPAR to LRP is required for clearance of uPA-PAI-1–occupied uPAR because internalization is blocked by incubation with recombinant D3. Moreover, uPA-dependent plasmin generation and the ability of HT1080 cells to migrate through Matrigel-coated invasion chambers are also inhibited in the presence of D3. These results demonstrate that GPI-anchored uPAR is endocytosed by piggybacking on LRP and that direct binding of occupied uPAR to LRP is essential for internalization of occupied uPAR, regeneration of unoccupied uPAR, plasmin generation, and invasion and migration through extracellular matrix.

Efeito das gorduras interesterificadas sobre o desenvolvimento da lesão aterosclerótica em camundongos knockout para o receptor de LDL

Nas últimas décadas, diversos estudos têm demonstrado os efeitos nocivos dos ácidos graxos trans à saúde. Consequentemente, diversas agências reguladoras de saúde e sociedades responsáveis pela elaboração de diretrizes nutricionais recomendaram a redução do consumo desses ácidos graxos. Deste modo, a indústria de alimentos vem adequando seus produtos a fim de substituir os ácidos graxos trans por gorduras interesterificadas, porém seus efeitos sobre o desenvolvimento da aterosclerose não foram ainda totalmente elucidados. Portanto, o objetivo deste estudo foi avaliar o efeito de gorduras interesterificadas contendo principalmente ácido graxo palmítico ou esteárico sobre o desenvolvimento da aterosclerose. Desta forma, camundongos knockout para o receptor de LDL (LDLr-KO) recém-desmamados foram alimentados por 16 semanas com dietas hiperlipídicas (40% do valor calórico total sob forma de gordura) contendo principalmente ácidos graxos poli-insaturados (POLI), trans (TRANS), palmítico (PALM), palmítico interesterificado (PALM INTER), esteárico (ESTEAR) ou esteárico interesterificado (ESTEAR INTER) para determinação de concentrações plasmáticas de colesterol total e triglicérides; perfil de lipoproteínas; conteúdo de lípides (Oil Red O) e colágeno (Picrosirius Red) e infiltrado de macrófagos (imuno-histoquímica) na área de lesão aterosclerótica; expressão e conteúdo proteico de citocinas na aorta; dosagem das citocinas secretadas por macrófagos de peritônio estimulados ou não com lipopolissacarídeo (LPS); efluxo celular de colesterol mediado pela apo-AI e HDL2. Os resultados mostraram que os animais que consumiram a gordura interesterificada contendo ácido palmítico (PALM INTER) desenvolveram importante lesão aterosclerótica em comparação aos grupos PALM, ESTEAR, ESTEAR INTER e POLI, resultados confirmados pelo conteúdo de colágeno na lesão. Apesar do processo de interesterificação não ter alterado as concentrações plasmáticas de lípides, conforme verificado entre os grupos PALM vs PALM INTER e ESTEAR vs ESTEAR INTER, o acúmulo de colesterol na partícula de LDL foi similar entre os grupos PALM INTER e TRANS. Além desse efeito sobre o perfil de lipoproteínas, macrófagos do peritônio de camundongos que consumiram PALM INTER secretaram significativamente mais IL-1beta, IL-6 e MCP-1 em comparação aos demais grupos. Esse efeito pró-inflamatório foi confirmado na aorta, onde se observou maior expressão de TNF-alfa e IL-1beta para o grupo PALM INTER em comparação a PALM. Tal insulto inflamatório foi similar ao provocado por TRANS. Esses efeitos deletérios do PALM INTER podem ser parcialmente atribuídos ao acúmulo de colesterol nos macrófagos, promovido pelo prejuízo no efluxo de colesterol mediado pela apo-AI e HDL2, bem como aumento da expressão de receptores envolvidos na captação de LDL modificada (Olr-1) e diminuição daqueles envolvidos na remoção intracelular de colesterol (Abca1 e Nr1h3) na parede arterial. Como conclusão, as gorduras interesterificadas contendo ácido palmítico favorecem o acúmulo de colesterol nas partículas de LDL e em macrófagos, ativando o processo inflamatório, o que conjuntamente contribuiu para maior desenvolvimento de lesão aterosclerótica

Uber die Beziehungen chronischer Blutdruckerhohung zur Blutkorperchenzahl und zum Hamoglobingehalt.

Mode of access: Internet.

Ueber die histologischen Veranderungen des Darmes bei Invagination : im Anschluss an einen Fall chronischer Invagination des untersten Ileum in das Coecum.

Mode of access: Internet.

Ueber einen fall von akuter arsenik-vergiftung.

Thesis (doctoral)--

Effects of LDL-immunoapheresis on plasma concentrations of vitamin E and carotenoids in patients with familial hypercholesterolemia

Recently very potent extracorporeal cholesterol-lowering treatment options have become available for patients with hypercholesterolemia. LDL immunoapheresis treatment selectively removes LDL and lipoprotein(a) from the circulation. Since LDL is the major carrier of lipophilic antioxidants in plasma, the purpose of the present study was to assess the effects of a single LDL apheresis treatment on plasma concentrations of tocopherols (alpha- and gamma-tocopherol) and carotenoids (alpha- and beta-carotene, zeaxanthin, cryptoxanthin, canthaxanthin, lycopene, and retinol). Plasma antioxidant concentrations were determined by HPLC in 7 patients with familial hypercholesterolemia before and after LDL immunoapheresis treatment. Plasma concentrations of both alpha- and gamma-tocopherol and the different carotenoids were significantly reduced by LDL apheresis. However, when standardized for cholesterol to adjust for cholesterol removal, alpha- and gamma-tocopherol, retinol, and the more polar carotenoids lutein and zeaxanthin increased in response to apheresis treatment, while the more unpolar carotenoids such as beta-carotene and lycopene did not change. These data demonstrate that a single LDL immunoapheresis treatment affects tocopherols and individual carotenoids differently. This may be explained by differences in chemical structure and preferential association with different lipoproteins. These results further imply that tocopherols, lutein, zeaxanthin, and retinol, are associated in part with lipoproteins and other carriers such as retinol-binding protein that are not removed during apheresis treatment. (C) 2004 Wiley-Liss, Inc.

Ceramides reduce CD36 cell surface expression and oxidised LDL uptake by monocytes and macrophages

Oxidised LDL accumulates in macrophages following scavenger receptor (SR) uptake. The expression of the SR, CD36, is increased by oxidised LDL. The signalling molecule, ceramide, can modulate intracellular peroxides and increase lipid peroxidation. Ceramide also accumulates in atherosclerotic plaques. Thus, we have examined whether ceramide can modulate CD36 expression and function in human monocyte/macrophages. Addition of synthetic short chain ceramides or the action of sphingomyelinase to generate physiological long chain ceramides in situ caused significant reductions in CD36 expression by monocytes/macrophages which was not due to inhibition of mRNA expression. Inhibition of proteasomal degradation using lactacystin had no effect on CD36 expression, however, flow cytometric analysis of permeabilised cells suggested an intracellular trafficking blockade. Ceramide treated monocytes/macrophages showed dose dependent reduction in oxidised LDL uptake. Taken together, it is suggested that ceramide blocks the transport of CD36 to the membrane of monocytes/macrophages, thereby preventing uptake of oxidised LDL. © 2006 Elsevier Inc. All rights reserved.

Homocysteine from endothelial cells promotes LDL nitration and scavenger receptor uptake

We recently reported that methionine-loaded human umbilical vein endothelial cells (HUVECs) exported homocysteine (Hcy) and were associated with hydroxyl radical generation and oxidation of lipids in LDL. Herein we have analysed the Hcy-induced posttranslational modifications (PTMs) of LDL protein. PTMs have been characterised using electrophoretic mobility shift, protein carbonyl ELISA, HPLC with electrochemical detection and Western blotting of 3-nitrotyrosine, and LDL uptake by scavenger receptors on monocyte/macrophages. We have also analysed PTMs in LDL isolated from rheumatoid (RA) and osteo-(OA) arthritis patients with cardiovascular disease (CVD). While reagent Hcy (<50 μM) promoted copper-catalysed LDL protein oxidation, Hcy released from methionine-loaded HUVECs promoted LDL protein nitration. In addition, LDL nitration was associated with enhanced monocyte/macrophage uptake when compared with LDL oxidation. LDL protein nitration and uptake by monocytes, but not carbonyl formation, was elevated in both RA and OA patients with CVD compared with disease-matched patients that had no evidence of CVD. Moreover, a direct correlation between plasma total Hcy (tHcy) and LDL uptake was observed. The present studies suggest that elevated plasma tHcy may promote LDL nitration and increased scavenger receptor uptake, providing a molecular mechanism that may contribute to the clinical link between CVD and elevated plasma tHcy. © 2005 Elsevier Inc. All rights reserved.