bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of activation on lipid and lipoprotein metabolism in murine macrophages.
Authors: Kraemer F B , Tavangar K , Gandjei R K , Kirlew K , Behr S R
Published: June 2011

The effects of activation on lipid and lipoprotein metabolism were examined in resident murine macrophages, inflammatory cells elicited by thioglycolate, primed cells elicited by pyran copolymer, and activated cells elicited by Corynebacterium parvum. Low density lipoprotein receptors were reduced by 70%, while scavenger receptors were reduced 60% in activated cells. Basal cholesteryl ester and triglyceride synthesis were increased fourfold in activated cells, whereas the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase was high in resident cells and progressively declined by greater than 80% in activated cells. Activities of neutral cholesteryl esterase and neutral triglyceride lipase were increased two- to fourfold in inflammatory, primed, and activated macrophages. These results demonstrate the diverse changes in lipid and lipoprotein metabolism that occur with activation and emphasize how the behavior of macrophages in atherosclerotic lesions can be altered by activation.
Macromolecular transport across arterial and venous endothelium in rats. Studies with Evans blue-albumin and horseradish peroxidase.
Authors: Chuang P T , Cheng H J , Lin S J , Jan K M , Lee M M , Chien S
Published: June 2011

Atherosclerotic lesions are characterized by lipid infiltration in regions with high rates of endothelial cell turnover. The present investigation was designed to elucidate the route of macromolecular transport across vascular endothelium. The aorta and vena cava of male Sprague-Dawley rats were perfusion-fixed after the intravenous injection of Evans-blue albumin (EBA) or horseradish peroxidase (HRP). Fluorescence microscopic examination of en face preparation of the aorta stained with hematoxylin allowed the identification of endothelial cells that underwent mitosis, together with the localization and quantification of fluorescent spots for EBA leakage. The HRP specimens were subjected to histochemical treatment, and HRP leakage was seen as brown spots under the light microscope. Silver nitrate stain was added in both EBA and HRP studies to outline cell boundaries and to visualize stigmata, stomata, and dead cells. In the aorta, almost every dividing cell showed junctional leakage to albumin and HRP, with clustering of leaky spots around the branch orifices. Time-dependent studies showed gradual increases in the diameter and number of these heterogeneously sized leaky spots, which finally fused to sizes corresponding to the "blue areas" for EBA or "brown areas" for HRP. Compared with arteries, veins had fewer mitotic cells, but more dead cells and diffuse dye-staining areas, indicating a more rapid transport of macromolecules. The leaky spots in the artery were associated mainly with mitotic cells, dead cells, and stigmata, whereas those in the vein occurred primarily at regions with dead cells. These results suggest that the preferential association of the enhanced transport of macromolecules with mitosis in the arterial as compared to venous endothelium and the differential behavior in transmural transport between arteries and veins may form the basis for the predilection of atherosclerosis in arteries.
Noninvasive imaging of 99mtechnetium-labeled low density lipoprotein uptake by tendon xanthomas in hypercholesterolemic patients.
Authors: Ginsberg H N , Goldsmith S J , Vallabhajosula S
Published: June 2011

Technetium-labeled low density lipoproteins (Tc-LDL) appear to be useful for describing LDL biodistribution in normal and dyslipidemic subjects. We injected 99mTc-LDL into subjects with large tendon xanthomas secondary to homozygous familial hypercholesterolemia or sitosterolemia. Rapid (4 hours) accumulation of Tc-99m activity in xanthomas was observed, and this accumulation increased over a 24-hour period. No comparable accumulations of Tc-99m activity were noted in normal subjects or in a subject with heterozygous familial hypercholesterolemia who had very small tendon xanthomas. These findings support previous biopsy data indicating active uptake of LDL by macrophages within xanthoma and suggest that 99mTc-LDL imaging of xanthomas may be useful in studies of the effects of diet and drugs on the accumulation of lipoproteins by atherosclerotic plaques.
Relationship between sensitivity to dietary fat and dietary cholesterol.
Authors: Clifton P M , Kestin M , Abbey M , Drysdale M , Nestel P J
Published: June 2011

A group of 56 hypercholesterolemic and normocholesterolemic men and women were given approximately 700 mg a day of egg yolk cholesterol in a double-blind, crossover study while they were on a background diet containing approximately 30% of energy as fat. Overall there was a 0.23 mmol/l rise in plasma cholesterol (3.7%, p less than 0.001) after 4 weeks, a 0.19 mmol/l rise in low density lipoprotein (LDL) cholesterol (4.9%, p = 0.002), and a 0.07 mmol/l rise in high density lipoprotein (HDL) cholesterol (5.4%, p less than 0.001). Plasma triglycerides fell by 0.07 mmol/l (5.1%). Normocholesterolemic individuals (plasma cholesterol less than 5.2 mmol/l) experienced small, nonsignificant rises of 0.06, 0.02, and 0.05 mmol/l in total, LDL, and HDL cholesterol, respectively. Hypercholesterolemic subjects were classified on the basis of their response to a low fat diet. Diet-sensitive subjects were defined by a greater than 10% fall in plasma cholesterol on a 25% fat, low cholesterol (less than 200 mg/day) diet. These individuals were found to be more responsive to the effect of dietary cholesterol than were diet-insensitive subjects; the respective changes in the two groups were rises of 0.36 mmol/l versus 0.19 mmol/l in plasma cholesterol (p = 0.06) and rises of 0.30 versus 0.15 mmol/l in LDL cholesterol (p = 0.06). In addition to elevating HDL cholesterol by 0.09 mmol/l and 0.07 mmol/l, respectively, dietary cholesterol also produced an increase in the proportion of HDL2, from 40% to 44% of HDL protein (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Postprandial lipemia and lipoprotein lipase in the rabbit are modified by olive and coconut oil.
Authors: Van Heek M , Zilversmit D B
Published: June 2011

Feeding a 14% coconut oil/0.5% cholesterol (CNO/chol) diet to rabbits resulted in plasma triglycerides that were, on average, 15 times higher than basal levels. Plasma triglycerides in rabbits fed a 14% olive oil/0.5% cholesterol (OO/chol) diet were significantly below baseline levels. Differences in postprandial triglyceride response and postheparin plasma lipoprotein lipase activity (LPL) in various feeding conditions were studied to determine the mechanism of the hypertriglyceridemia. Postprandial triglyceride responses after the first high fat/cholesterol meal were more prolonged in CNO/chol rabbits than in OO/chol rabbits; postprandial triglyceride responses after chronic CNO/chol feeding were significantly greater compared to OO/chol rabbits. When long-term CNO/chol rabbits were given one OO/chol or corn oil/chol meal, postprandial triglyceride peaks were greatly diminished, suggesting that these unsaturated fat meals may alter triglyceride clearance capacity. LPL activity was 400% higher than basal levels in chronically fed OO/chol rabbits but changed very little in chronically fed CNO/chol rabbits. Twenty-four hours after a single OO/chol meal was fed to chow-fed rabbits, LPL doubled; one CNO/chol meal was associated with only a 40% increase. Feeding a single OO/chol or corn oil/chol meal to chronically fed CNO/chol rabbits resulted in a 30% to 50% increase in LPL by 24 hours. Thus, the hypertriglyceridemia in CNO/chol rabbits may result in part from a decreased clearance capacity due to a lack of increase in LPL activity, while increased LPL may be partially responsible for the hypotriglyceridemia observed in OO/chol feeding. Aortic cholesterol was substantially higher in CNO/chol rabbits. Triglyceride was approximately eight times greater in livers from CNO/chol-fed rabbits than in those fed OO/chol, but liver cholesterol was only about one-third as much as that in OO/chol rabbits.
Different efflux pathways for high and low density lipoproteins from porcine aortic intima.
Authors: Nordestgaard B G , Hjelms E , Stender S , Kjeldsen K
Published: June 2011

To study the efflux of high (HDL) and low (LDL) density lipoproteins from the arterial wall in vivo, a surgical model in pigs was used. An isolated segment of the lesion-free thoracic aorta was pulse labeled from the lumen of the artery with 3H-cholesteryl ester labeled HDL and 14C-cholesteryl ester labeled LDL. Subsequently, the labeled aortic segment was exposed to cold chase in vivo. The transfer of HDL cholesteryl ester from plasma into intima expressed as intimal clearance was three to seven times greater than that of LDL cholesteryl ester. At least 50%, but possibly as much as 95%, of the HDL cholesteryl ester that entered the arterial intima during a period of 4 hours penetrated the arterial wall beyond the internal elastic lamina. In contrast, less than 15% of the LDL cholesteryl ester that entered the arterial intima in the same period penetrated beyond the luminal layer. After 24 hours of cold chase in vivo, more than 80% of both labeled HDL esterified cholesterol and labeled LDL esterified cholesterol had disappeared from the arterial wall. Transmural profiles after 9 hours of cold chase showed that labeled HDL was present throughout the entire arterial wall, whereas labeled LDL in quantitative amounts was present only in the luminal layer. The results suggest that the most important efflux route for HDL esterified cholesterol is through the vasa vasorum and lymphatics in the outer media and adventitia, whereas LDL esterified cholesterol predominantly leaves intima via the lumen of the artery.
Cholesterol and coronary heart disease mortality. A 23-year follow-up study of 9902 men in Israel.
Authors: Goldbourt U , Yaari S
Published: June 2011

A 23-year follow-up study of 10,059 40- to 65-year-old participants in the Israeli Ischemic Heart Disease Study found that of 3473 deaths (34.5%), in 1098 (10.9%) coronary heart disease (CHD) was the underlying cause. Total serum cholesterol (TC) was measured in 9902 individuals. During the study, CHD mortality was elevated primarily in individuals in quintiles 4 and 5 (TC levels greater than or equal to 217 mg/dl). Although CHD mortality increased marginally with increasing TC at levels below 217 mg/dl, this was entirely explained by age and other correlated risk factors in a multivariate adjustment of the survival curves. The "net" 23-year survival in terms of CHD was 87% in quintile 5 (TC greater than 241) versus 93% in quintile 1 (TC less than 176 mg/dl). CHD mortality was inversely related to the percent of cholesterol in high density lipoprotein (PHDL). All-cause mortality increased only when TC was above 240 mg/dl and in the subjects with PHDL levels in the lowest 20%. Lipids appeared to be somewhat less effective in predicting subsequent CHD mortality than did hypertension and smoking and were clearly secondary in assessing risk of all-cause death. The results raise the question whether intensive treatment for hypercholesterolemia is indicated for men at "borderline" levels. We conclude that the association between serum cholesterol and long-term mortality partly reflects the role that levels of co-existing CHD risk factors play in prognosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Macrophage and smooth muscle cell proliferation in atherosclerotic lesions of WHHL and comparably hypercholesterolemic fat-fed rabbits.
Authors: Rosenfeld M E , Ross R
Published: June 2011

Lesions of atherosclerosis were analyzed at varying stages of development in Watanabe heritable hyperlipidemic (WHHL) and comparably hypercholesterolemic fat-fed (FF) rabbits for the capacity to incorporate thymidine into proliferating cells within both the intima and the underlying media. An identical inverse relationship between the intimal/medial ratio (which reflects both lesion size and severity) and the labeling index was observed for both the WHHL and FF rabbits. Analysis of the spatial distribution of the labeled cells within each lesion revealed the highest rates of thymidine incorporation in cells situated within the superficial areas and lateral margins of the lesions. Up to 12% of the labeled cells were foam cells, which were predominantly located immediately beneath the endothelium and within the lateral margins. Some labeled macrophages were also observed within the necrotic core of advanced lesions. There were no differences in the labeling indexes at differing sites in the aorta, providing lesions of comparable size were compared. Simultaneous thymidine autoradiography and immunostaining with cell type-specific monoclonal antibodies revealed that approximately 30% of the labeled cells were macrophages and 45% were smooth muscle cells in advanced lesions from both WHHL and FF rabbits.
Lipoprotein lipase and hepatic triacylglycerol lipase activities in peripheral and skeletal muscle lymph.
Authors: Huang J , Sloop C H , Roheim P S , Wong L
Published: June 2011

We studied the interstitial fluid concentration of two lipid-metabolizing enzymes (lipoprotein lipase and hepatic triacylglycerol lipase) to determine their importance in interstitial modification of filtered lipoproteins. Despite the use of a very sensitive lipase assay (1 nmol of fatty acid release/ml/hr), lipase activities in plasma and in peripheral and skeletal muscle lymph from control dogs were below the sensitivity of our assay. After heparin injection, hepatic triacylglycerol lipase and lipoprotein lipase activities in plasma were similar. However, the postheparin hepatic triacylglycerol lipase activities in peripheral and skeletal muscle lymph were only 1.4% and 1.1%, respectively, those of plasma. This concentration is considerably less than the lymph concentration of albumin, which has a similar size to the lipases but has a lymph concentration of 30% to 40% of plasma. Lipoprotein lipase activity in peripheral lymph and skeletal muscle lymph was 2.7% and 4.8%, respectively, of plasma activity. Since lipoprotein lipase has a similar size as hepatic triacylglycerol lipase, the disproportionate amount of lipoprotein lipase in lymph as compared to hepatic triacylglycerol lipase could be due to heparin crossing the capillary endothelium and displacing lipoprotein lipase from peripheral cells. Injection of radioactive heparin confirmed that it does cross into the interstitial space in sufficient concentrations to displace lipase from peripheral cells. We conclude that most of the lipase found in lymph after heparin injection is derived from peripheral cells and not from plasma. Furthermore, hepatic triacylglycerol lipase does not play a role in high density lipoprotein remodeling in interstitial fluid. Therefore, it seems likely that the considerable remodeling of high density lipoprotein that we found previously results from its interaction with peripheral cells.
Effect of dietary magnesium on development of atherosclerosis in cholesterol-fed rabbits.
Authors: Ouchi Y , Tabata R E , Stergiopoulos K , Sato F , Hattori A , Orimo H
Published: June 2011

The effect of dietary magnesium (Mg) on the development of atherosclerosis in cholesterol-fed rabbits was investigated. Male New Zealand White rabbits (n = 31) were placed on five kinds of diets: regular, 1% cholesterol, and 1% cholesterol diets supplemented with either 300, 600, or 900 mg (as Mg) of Mg sulfate. The regular and 1% cholesterol diets contained 400 mg of Mg per 100 g. Each rabbit received 100 g daily of the appropriate diet. Additional Mg was well tolerated and did not affect blood pressure or body weight. The rabbits were sacrificed after 10 weeks, and the oil red O-positive atherosclerotic area that covered the aortic intima and the cholesterol content of the aorta was measured. Additional Mg decreased both the area of the aortic lesions and the cholesterol content of the aortas in a dose-dependent manner. The 1% cholesterol diet significantly increased plasma cholesterol and triglyceride concentrations and decreased high density lipoprotein (HDL) cholesterol concentration. Additional Mg had no further effect on cholesterol and HDL cholesterol concentrations, but it slightly decreased the rise in triglyceride concentration. These results indicate that dietary Mg prevents the development of atherosclerosis in cholesterol-fed rabbits by inhibiting lipid accumulation in the aortic wall.
Nucleotide profiles in normal minipig arterial tissue.
Authors: Pap J M , Hammer D F , Fry D L , Kelley R E , Altschuld R A
Published: June 2011

The purpose of this study was to characterize the nucleotide profiles of a normal porcine elastic and muscular artery. Tissue samples (50 to 150 mg) were excised from the descending thoracic aorta and from the femoral artery of 14 normocholesterolemic, anesthetized minipigs. In three animals, transmural myocardial samples were also obtained. Nucleotide and nucleoside concentrations were analyzed by using a recently developed ion-pairing, reverse-phase, high-performance liquid chromatographic method. The arterial samples contained relatively low concentrations of adenosine triphosphate, approximately one-eighth that of the myocardial counterpart. Relative to the femoral artery, the aortic samples had significantly lower adenylate energy charges and higher levels of adenosine diphosphate, adenosine monophosphate, adenosine, and inosine. These baseline aortic levels did not change after in vitro exposure to 95% oxygen. The different energy states observed in the two arteries may reflect functional or metabolic differences in their medial smooth muscle cell populations. Alternatively, the lower energy state observed in the thicker walled aorta may be a manifestation of inadequate medial oxygen delivery that persists despite oxygen enrichment in vitro. We conclude that arterial energy states exhibit regional variation. This information will serve as a point of departure for the investigation of the role energy states may play in the atherosclerotic process.
Regulation of hepatic high density lipoprotein binding proteins after administration of simvastatin and cholestyramine to rats.
Authors: Mathai D , Fidge N , Tozuka M , Mitchell A
Published: June 2011

We investigated the regulation of putative high density lipoprotein (HDL) receptors in rat liver after cholesterol feeding and the administration of cholesterol-lowering drugs to rats. The expression of two plasma membrane HDL binding proteins (HB1 and HB2) were compared in control and treated livers by first separating membrane proteins on sodium dodecyl sulfate-polyacrylamide gels and quantitating HB1 and HB2 levels with a specific ligand blot assay. Of the various treatments used, only simvastatin or simvastatin plus cholestyramine produced significant changes, with reductions of up to 40% and 60%, respectively, for HB1 and HB2. The effect on the binding proteins was not associated with changes in serum cholesterol concentrations, which did not change significantly after either treatment, although a marked rise in liver cholesterol concentration after cholesterol was associated with a moderate increase in HB2 expression. We show evidence for regulation of the levels of hepatic HDL binding proteins and provide another important criterion for the acceptance of HB1 and HB2 as components of a functional HDL receptor.
Changes in plasma factor VIII complex and serum lipid profile during atherogenesis in cynomolgus monkeys.
Authors: Baron B W , Lyon R T , Zarins C K , Glagov S , Baron J M
Published: June 2011

If endothelial injury plays a prominent role in early atherogenesis, the plasma levels of von Willebrand factor (VWF), which is made within and normally released from endothelial cells, might be expected to rise as a marker of the cellular damage. To evaluate this hypothesis, we measured plasma VWF (as VIIIR:Ag), factor VIII:C, and serum lipids serially up to 37 weeks in 29 adult male cynomolgus monkeys on an atherogenic diet. Factor VIII:C peaked at 113% above baseline by week 10 (p less than 0.0001), then fell and remained 53% below baseline (p less than 0.04) during weeks 20 to 37. However, the overall rise in VWF was not significant. In contrast, serum cholesterol continued to rise after week 21. Serum phospholipids (PL), triglycerides (TG), and free fatty acids (FFA) showed a temporal pattern similar to VIII:C. Significant positive correlations with VIII:C were noted for PL (r = 0.59, p = 0.0001) and TG (r = 0.36, p = 0.0096). At autopsy, small to moderately advanced atherosclerotic lesions were distributed throughout the aortas of the majority of the animals. We conclude that changes in plasma VIIIR:Ag do not correlate with atherogenesis in this model. However, the similar course of VIII:C, TG, and PL suggests that these substances may be involved and perhaps interrelated early in atherogenesis.
Effect of dietary fish oil on coronary artery and aortic atherosclerosis in African green monkeys.
Authors: Parks J S , Kaduck-Sawyer J , Bullock B C , Rudel L L
Published: June 2011

Studies were carried out for 2.5 to 3 years in adult male African green monkeys (grivet subspecies) fed diets containing 22% of calories as lard or fish oil with 40% of calories as fat and 0.75 mg cholesterol/Kcal to determine if isocaloric substitution of menhaden fish oil for lard affects coronary artery atherosclerosis. The average total plasma cholesterol concentrations during the experimental period were significantly lower for the fish-oil group (231 +/- 37 mg/dl) compared to the lard group (360 +/- 44 mg/dl), but this difference did not become apparent until after 5 months of experimental diet consumption. High density lipoprotein cholesterol concentrations were 30% lower (p less than 0.01) for the fish-oil group also (57 +/- 5 vs. 82 +/- 6 mg/dl). Plasma triglyceride concentrations were low for both groups, but after about 5 months of diet consumption, they were higher for the animals fed fish oil (25 +/- 2 mg/dl) compared to their lard-fed counterparts (15 +/- 1 mg/dl). Coronary artery intimal area (in this case a measure of early atherosclerotic lesion size) was low in all animals but was significantly less (p less than 0.03) for the fish oil vs. lard groups (0.01 +/- 0.002 vs. 0.03 +/- 0.009 mm2). More atherosclerosis was found in other arteries, and a trend was seen of less atherosclerosis in the thoracic aorta and common carotid arteries of the fish-oil group. The size of lesions in the abdominal aorta was similar between diet groups, but microscopic examination of arteries of the lard group revealed relatively more cholesterol monohydrate crystals compared to the arteries of the fish-oil group. Chemical analysis showed that there was less esterified cholesterol (1.46 +/- 0.71 vs. 3.43 +/- 0.74 mg/g, p = 0.04) and free cholesterol (3.7 +/- 2.15 vs. 7.05 +/- 1.68 mg/g, p = 0.08) in the abdominal aortas taken from the animals fed fish oil. There was a significant correlation between low density lipoprotein (LDL) cholesteryl ester (CE) fatty acid ratio (i.e., saturated + monounsaturated/polyunsaturated species) and the amount of esterified (r = 0.59) and free (r = 0.63) cholesterol in the abdominal aortas. Compared to the lard group, animals fed fish oil had significantly lower LDL CE melting temperatures (26 +/- 1 vs. 38 +/- 1 degree C) and significantly smaller LDL particles (2.68 +/- 0.10 vs. 3.25 +/- 0.38 g/mumol). Therefore, the potentially antiatherogenic effects of dietary fish oil include its ability to decrease the concentration, size, CE content, and CE melting temperature of plasma LDL.
Role of elastase and lysyl oxidase activity in spontaneous rupture of internal elastic lamina in rats.
Authors: Osborne-Pellegrin M J , Farjanel J , Hornebeck W
Published: June 2011

Rupture of the internal elastic lamina may occur spontaneously with age in certain arteries of the rat and to various extents in different strains. This phenomenon may have some bearing on certain aspects of arterial pathology. For this study, we investigated biochemically the mechanisms of formation of interruptions in the internal elastic lamina (IIEL) by comparing aortas of Brown Norway (BN) rats, which develop numerous IIEL in the abdominal aorta, with those of Long-Evans (LE) rats, which develop none. We isolated aortic elastin from BN and LE rats and determined its amino acid composition and its susceptibility to different elastases. No differences were found between the two strains, but the quantity of elastin isolated per aorta was lower in the BN than in the LE rats. Elastase-like activity (ELA) of whole aortic extracts, measured with Suc(Ala)3NA as a substrate, was greater in the BN rats than in the LE rats of both sexes. The assay of ELA in endothelium, media, and adventitia extracted separately showed very low levels in the media compared to the endothelium and adventitia. The endothelium accounts for about one-half of the total aortic ELA, but a difference between the two strains was detected only in the adventitia. With 3H-insoluble elastins prepared from BN and LE aortas as substrates, elastinolytic activity (EA) was detected only in extracts of endothelium after prior exposure to trypsin. Extracts from BN endothelium on BN elastin were more active than were those from LE endothelium on LE elastin. The assay of lysyl oxidase activity in aortic extracts from the two strains with 3H-collagen from chick embryo calvaria as the substrate showed a lower activity in the BN than in the LE rats. Taken together, these results suggest that increased elastase activity and decreased lysyl oxidase activity may be involved in the formation of IIEL.
Interaction of low density lipoproteins with human aortic elastin.
Authors: Podet E J , Shaffer D R , Gianturco S H , Bradley W A , Yang C Y , Guyton J R
Published: June 2011

Interaction between lipoproteins and elastin in the arterial wall may play an important role in atherosclerotic lipid deposition, but binding affinities and other characteristics of the interaction have not been determined previously. Elastin was isolated by hot alkali treatment of human aortic tissue. At 4 degrees C, radioiodinated human low density lipoprotein (LDL) bound to more than one class of binding sites on elastin. Sites of highest affinity had an apparent dissociation constant of 3.6 x 10(-8) M. Total binding at an LDL concentration of 50 micrograms/ml ranged from 4 to 50 ng LDL protein/mg elastin. The binding was relatively specific, since binding was competitively inhibited by LDL and apo E-containing high density lipoprotein (HDL) but only modestly by HDL3. Atherosclerotic elastin exhibited a twofold to fourfold higher capacity for binding LDL, but a reduced affinity. At 37 degrees C, normal elastin exhibited an initial rapid binding of LDL, with a slower linear phase of binding over a 15-hour period, indicating an additional complex process at this temperature. Consideration of the expected LDL concentrations in the arterial intima, in comparison with binding affinities, suggests that LDL binding to elastin probably occurs in the intima and may foster atherosclerotic lipid deposition.
Passage state affects arachidonic acid content and eicosanoid release in porcine aortic endothelial cells.
Authors: Brown M L , Deykin D
Published: June 2011

Porcine aortic endothelial cells were cultured through four passages from primary cultures. The arachidonic acid content of individual phospholipid classes and the release of 6-keto-prostaglandin F1 alpha and 15-hydroxyeicosatetraenoic acid in response to 1 microM ionophore A23187 were assayed at each passage. The content of arachidonic acid in phosphatidylinositol and diacyl phosphatidylethanolamine remained constant at passage 1 but declined at passage 2 by approximately 29% and at passage 4 by approximately 59%. The release of 6-keto-prostaglandin F1 alpha was also unchanged at passage 1 but decreased by 60% at passage 2 and by 82% from its original value at passage 4. In contrast, the arachidonic acid content of diacyl phosphatidylcholine and of alkenyl phosphatidylethanolamine decreased with each passage, by 34% at passage 1, 59% at passage 2, 71% at passage 3, and 76% of the original value at passage 4. Stimulation with arachidonic acid reversed the passage effect. The release of 15-hydroxyeicosatetraenoic acid decreased by 82% at passage 1 and diminished to a 97% decrement from the original value by passage 4. When stimulated with arachidonic acid, 15-hydroxyeicosatetraenoic acid steadily decreased by approximately 70% at passages 3 and 4. The data indicate that passage state strikingly and nonuniformly affects phospholipid class arachidonic acid content and eicosanoid release in response to agonist stimulation.
High density lipoproteins and coronary atherosclerosis. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients.
Authors: Johansson J , Carlson L A , Landou C , Hamsten A
Published: June 2011

The relations of high density lipoprotein (HDL) subclasses to severity and rate of progression of coronary atherosclerosis were investigated in 60 men who had survived a myocardial infarction before the age of 45 years and who had subsequently undergone two coronary angiographies, with an intervening time interval of 4-7 years between angiographies. Five HDL subclasses with different particle sizes were determined by gradient gel electrophoresis, and the major serum lipoprotein classes were separated by preparative ultracentrifugation in connection with the second angiography. Highly significant inverse correlations were found between the plasma levels of the largest HDL particles, the HDL2b subclass, and both disease severity as observed on the second coronary angiogram (r = -0.53, p less than 0.001) and progression of coronary lesions between angiographies (r = -0.38, p less than 0.01). Grouping the patients according to the presence or absence of very low density lipoprotein (VLDL) triglyceride elevation revealed striking differences in the relations of HDL subspecies to coronary atherosclerosis between normotriglyceridemic and hypertriglyceridemic subjects. There were strong inverse correlations between the plasma HDL2b concentration and both severity of lesions (r = -0.72, p less than 0.001) and rate of lesion progression (r = -0.58, p less than 0.01) in the normotriglyceridemic patients, whereas this relation was absent in subjects with hypertriglyceridemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of n-3 and n-6 fatty acid-enriched diets on plasma lipoproteins and apolipoproteins in heterozygous familial hypercholesterolemia.
Authors: Friday K E , Failor R A , Childs M T , Bierman E L
Published: June 2011

Polyunsaturated fatty acids in vegetable (n-6) and marine (n-3) oils have been shown to reduce cholesterol levels in normolipidemic individuals. However, there is relatively little information available on the lipoprotein responses to dietary n-6 and n-3 fatty acids in individuals with genetic forms of hyperlipidemia at risk for premature cardiovascular disease. We studied five subjects with heterozygous familial hypercholesterolemia (FH), as well as five normal controls, on three rigidly controlled diets differing primarily in their fatty acid composition. FH subjects reduced their total plasma cholesterol by 34% during the n-3 diet and by 26% with the n-6 diet (both p less than 0.001) when compared with values while on a butter diet. In addition, low density lipoprotein (LDL) cholesterol fell 31% and 29% (both p less than 0.001), and apolipoprotein B (apo B) levels dropped 28% and 27% (both p less than 0.01) during the n-3 and n-6 diets, respectively. A significant reduction of total and LDL cholesterol as well as of apo B was also noted in normal controls during n-3 and n-6 diets. Total plasma triglyceride and high density lipoprotein cholesterol fell significantly during n-3 diets in normal and FH subjects. Thus, FH and normal subjects respond in a similar fashion to diets low in saturated fatty acids and rich in n-3 and n-6, with decreased LDL cholesterol and apo B concentrations.
Evaluation of human panelists in assessing coronary atherosclerosis.
Authors: Azen S P , Cashin-Hemphill L , Pogoda J , Mack W J , Sanmarco M E , Wickham E , Blankenhorn D H
Published: June 2011

The Cholesterol Lowering Atherosclerosis Study, a randomized, angiographic clinical trial, has demonstrated the beneficial effect of niacin/colestipol therapy on coronary and femoral atherosclerosis. The primary outcome was a panel-determined consensus score evaluating global coronary changes determined angiographically at 2 years. This article presents an evaluation of interreader agreement in independently assessing the status of native coronary arteries and overall coronary condition. Parameters include 1) identification of the presence of lesions and lesion changes; 2) estimation of lesion severity (percent stenosis) and amount of change in lesion severity; and 3) global assessment of change in coronary status. Readers independently agreed on 1) presence of lesions (82%) and change in lesions (51%); 2) percent stenosis +/- 10% (76%) and change in stenosis +/- 10% (81%); and 3) global assessment of change in coronary status within one step (96%). Results of these analyses may be useful in effectively designing angiographic trials that use a panel of human evaluators as well as computerized methods for angiographic interpretation.
High density lipoprotein apolipoproteins mediate removal of sterol from intracellular pools but not from plasma membranes of cholesterol-loaded fibroblasts.
Authors: Oram J F , Mendez A J , Slotte J P , Johnson T F
Published: June 2011

Cultured cells possess high-affinity binding sites (receptors) for high density lipoprotein (HDL) that appear to mediate removal of excess intracellular cholesterol from cells. To examine the role of intact HDL apoproteins in receptor-mediated cholesterol removal, HDL3 apoproteins were digested with the proteolytic enzymes trypsin and pronase, and the residual particles were used in sterol efflux experiments. Protease treatment abolished the interaction of HDL3 with the 110-kd cell membrane protein postulated to represent the HDL receptor molecule, indicating that this interaction is mediated by HDL apoproteins rather than lipids. Compared with native HDL3 protease-modified HDL3 had a markedly reduced ability to selectively remove sterol from intracellular pools, even though modified particles promoted greater cholesterol efflux from the plasma membrane than did native particles. These results indicate that whereas sterol efflux from plasma membranes is mediated by HDL lipids, removal of excess intracellular sterol from cells is mediated by HDL apoproteins. These findings are consistent with the hypothesis that receptor binding of HDL apoproteins stimulates translocation of excess intracellular sterol to the cell surface where it becomes accessible for removal by HDL or other lipid-rich acceptor particles.
Increase in plasma cholesteryl ester transfer protein during probucol treatment. Relation to changes in high density lipoprotein composition.
Authors: McPherson R , Hogue M , Milne R W , Tall A R , Marcel Y L
Published: June 2011

Probucol is a hypolipidemic agent that causes a marked decrease in high density lipoprotein (HDL) cholesterol. To investigate the mechanism of this effect, two studies were performed in hypercholesterolemic patients who had been stabilized previously on diet and were not receiving other lipid-lowering medication. Plasma cholesteryl ester transfer protein (CETP) concentrations were measured in fasting plasma samples before and after 10 weeks of probucol therapy using a sensitive and specific radioimmunoassay. Plasma total and low density lipoprotein cholesterol concentrations decreased, whereas apolipoprotein (apo) B was unchanged. Plasma apo E concentrations increased markedly. HDL cholesterol and apo A-I decreased in all subjects. These effects of probucol were accompanied by even more striking changes in plasma CETP concentrations, which increased by a mean of 64%. In a second study of six hypercholesterolemic subjects, the time-course effects of probucol on CETP and HDL subspecies were studied. Significant increases in plasma apo E and in CETP occurred after 4 weeks, and CETP, but not apo E, increased further after 16 weeks of treatment. Concomitant and opposite changes occurred in HDL composition, with decreases in HDL cholesterol and lipoprotein containing apo A-I. The increase in plasma CETP concentrations, the decrease in HDL cholesterol, and the increase in plasma apo E concentrations observed during probucol treatment are changes consistent with a postulated increase in reverse cholesterol transport via the remnant pathway.
Characterization of a human high density lipoprotein-associated protein, NA1/NA2. Identity with SP-40,40, an inhibitor of complement-mediated cytolysis.
Authors: James R W , Hochstrasser A C , Borghini I , Martin B , Pometta D , Hochstrasser D
Published: June 2011

Two peptides, NA1 and NA2, which we previously suggested to be associated with high density lipoproteins (HDLs), have been purified. Polyclonal antibodies against each peptide and a monoclonal antibody against NA2 have been used to further characterize them and their association with HDL. Immunoblotting studies revealed that the peptides form a complex of molecular mass of approximately 80 kd. Agarose gel filtration showed coelution of NA1/NA2 and apolipoprotein (apo) A-I, the structural protein of HDL. This was confirmed by fast protein liquid chromatography, which further indicated that up to 60% of NA1/NA2 was located within the lower density range of the HDL spectrum. Complementary studies with anti-apo A-I immunoaffinity columns provided evidence that at least 40% of NA1/NA2 was associated with HDL, an association easily disrupted by ultracentrifugal manipulation. Finally, partial amino acid sequences showed virtually complete homology with a recently identified protein, SP-40,40, or cytolysis inhibitor. The protein is suggested to have a powerful inhibitory effect on complement-mediated cell lysis. Our results could thus furnish an explanation for the previously observed modulating influence of HDL on complement activity.
Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease.
Authors: Groot P H , van Stiphout W A , Krauss X H , Jansen H , van Tol A , van Ramshorst E , Chin-On S , Hofman A , Cresswell S R , Havekes L
Published: June 2011

A delayed clearance of postprandial lipoproteins from the plasma may play a role in the etiology of premature coronary atherosclerosis. To address this hypothesis, we studied chylomicron (remnant) metabolism in two groups of 20 selected normolipidemic men aged 35-65 years, a group of coronary artery disease (CAD) patients, and a matched control group with documented minimal coronary atherosclerosis. Subjects received an oral fat load supplemented with cholesterol and retinyl palmitate. Plasma samples obtained during the next 24-hour period were analyzed for total as well as d less than 1.019 g/ml and d greater than 1.019 g/ml triacylglycerol, cholesterol, and retinyl ester concentrations. Although both groups of patients responded identically in terms of the appearance of gut-derived lipids in the plasma, CAD patients showed a marked delay in the clearance of retinyl esters as well as in the normalization of plasma triacylglycerol concentrations. Postheparin plasma hepatic lipase activity was significantly lower in the CAD group. Apolipoprotein E phenotype measurements did not reveal marked differences in frequency between both groups. The frequency distribution was not unusual in comparison with the normal Dutch population. The magnitude of the postprandial responses of triacylglycerol and retinyl esters was correlated positively with the fasting levels of plasma triacylglycerol and negatively with high density lipoprotein subfraction 2 cholesterol concentrations. These data indicate that the clearance of postprandial lipoproteins in normolipidemic CAD patients as selected in the present study is delayed as compared with that of controls without coronary atherosclerosis and suggest that postprandial lipoproteins may play a role in the etiology of their disease.
Asymptomatic atherosclerosis and insulin resistance.
Authors: Laakso M , Sarlund H , Salonen R , Suhonen M , Pyörälä K , Salonen J T , Karhapää P
Published: June 2011

High plasma insulin has been shown to be associated with the risk of coronary heart disease in nondiabetic subjects in prospective population studies. Furthermore, insulin resistance measured by the euglycemic glucose clamp technique has been shown to be related to lipid and lipoprotein changes favoring atherosclerosis and to high blood pressure. No study, however, has demonstrated that insulin resistance per se is directly associated with atherosclerosis. With this aim, we studied 30 middle-aged nonobese subjects with asymptomatic atherosclerosis in the femoral or carotid arteries and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were only slightly and nonsignificantly higher in subjects with atherosclerosis than in controls, and during the oral glucose tolerance test 1- and 2-hour glucose, insulin, and C-peptide levels were similar in both groups. During the euglycemic hyperinsulinemic (1,200 pmol/l) clamp studies, subjects with atherosclerosis had a 20% reduced whole-body glucose uptake (58 +/- 2 versus 71 +/- 4 mumol/kg/min, p = 0.004). Glucose oxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. In contrast, nonoxidative glucose disposal was significantly reduced in patients compared with that in controls (37 +/- 2 versus 50 +/- 4 mumol/kg/min, p = 0.004). When glucose uptakes were matched during the hyperglycemic clamp studies, the rate of nonoxidative glucose uptake was normalized in the patients. These results provide the first direct evidence that asymptomatic atherosclerosis is associated with insulin resistance. This insulin resistance is characterized by reduced whole-body and nonoxidative glucose uptake. In contrast, glucose and lipid oxidation, potassium disposal, and suppression of free fatty acid levels during hyperinsulinemia did not differ between the subjects with and without atherosclerosis.
Influences of common variants of apolipoprotein E on measures of lipid metabolism in a sample selected for health.
Authors: Xhignesse M , Lussier-Cacan S , Sing C F , Kessling A M , Davignon J
Published: June 2011

Five-hundred seventy-five white-collar workers (374 men; 99% Caucasians) aged 20-59 years were selected on the basis of their being healthy and clinically free from cardiovascular risk factors (except smoking and family history). We have observed a higher relative frequency of the epsilon 3 allele in this population, as is true of populations with a low prevalence of coronary heart disease. Each of the 11 plasma lipid and lipoprotein traits studied was adjusted for age, weight, height, body mass index, plasma glucose, and uric acid in men and women separately. The influence of each of the three common apo E alleles on each adjusted trait was evaluated by use of the average excess statistic. We established that in a population selected for health, the epsilon 2 allele is associated with lower plasma levels of total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B associated with LDL cholesterol in both men and women. Conversely, the epsilon 4 allele is associated with higher levels of these traits in women only. In contrast to the findings in populations not selected for health, the presence of the epsilon 2 allele in our subjects tended to be associated with lower and the epsilon 4 allele with higher plasma triglyceride levels. Finally and of particular note, the influence of the apolipoprotein E polymorphism on plasma measures of LDL metabolism is different in men and women. Specifically, the influence of the epsilon 4 allele is of greater magnitude in women. A part of this gender difference in allele effects on LDL metabolism in women is associated with the use of oral contraceptives and postmenopausal hormone replacement therapy.
Plasma concentrations of cholesteryl ester transfer protein in hyperlipoproteinemia. Relation to cholesteryl ester transfer protein activity and other lipoprotein variables.
Authors: McPherson R , Mann C J , Tall A R , Hogue M , Martin L , Milne R W , Marcel Y L
Published: June 2011

Cholesteryl ester transfer protein (CETP) mediates an important pathway for reverse cholesterol transport. Concentrations of CETP in fasting plasma were measured by radioimmunoassay in two different groups of hyperlipoproteinemic subjects. Plasma CETP concentrations measured by radioimmunoassay correlated closely with cholesterol ester transfer activity in normal plasma (r = 0.86). In the first group of 58 patients, plasma CETP concentrations were significantly increased, as compared with those in 79 normal subjects and in hypercholesterolemic (+26%) and combined hyperlipoproteinemic (+25%) subjects but were not altered in moderately hypertriglyceridemic subjects. Marked elevations in plasma CETP levels were documented in patients with dysbetalipoproteinemia (+68%) and severe chylomicronemia (+85%). Similar results were obtained in a second population of 50 hyperlipoproteinemic subjects. Significant correlations were found between plasma CETP levels and total cholesterol (r = 0.52), very low density lipoprotein (VLDL) cholesterol (r = 0.63), and apolipoprotein E concentration (r = 0.40). Correction of the lipoprotein phenotype by dietary means resulted in significant reductions in plasma CETP concentrations in patients with chylomicronemia and dysbetalipoproteinemia. In these subjects, plasma high density lipoprotein cholesterol concentrations increased as CETP decreased. These studies indicate that CETP levels increase in association with enhanced peripheral cholesterol transport via low density lipoprotein, beta-VLDL, or chylomicron remnants.
Metabolism of lipoprotein remnants in humans. Studies during intestinal infusion of fat and cholesterol in subjects with varying expression of the low density lipoprotein receptor.
Authors: Eriksson M , Angelin B , Henriksson P , Ericsson S , Vitols S , Berglund L
Published: June 2011

To study the possible importance of the low density lipoprotein (LDL) receptor in regulating the degree of postprandial lipemia, a cholesterol-rich fat emulsion was infused into the duodenum of subjects who were divided into four groups based on the expected variation in the expression of the LDL receptor: young men (n = 11), elderly men (n = 7), male patients on estrogen therapy (n = 5), and patients with familial hypercholesterolemia (n = 9). In familial hypercholesterolemia, fasting plasma levels of lipoproteins of d less than 1.006 g/ml, intermediate density lipoproteins, and LDLs were increased. During the fat infusion, the cholesterol and triglyceride contents in the d less than 1.006 g/ml fraction increased to a similar extent in all groups, whereas a concomitant reduction of LDL cholesterol levels was observed. The degree of the decrease in LDL cholesterol was positively correlated with the observed increase in triglycerides in the d less than 1.006 g/ml fraction. There were no signs of accumulation of intermediate density lipoproteins during infusion in any of the groups studied. The results indicate that the capacity for clearance of chylomicrons and chylomicron remnants is not affected by variation in LDL receptor expression.