bluuebunny/crossref_metadata_2025 huggingface dataset:
High density lipoprotein subfractions and coronary risk factors in normal men.
Authors: Robinson D , Ferns G A , Bevan E A , Stocks J , Williams P T , Galton D J
Published: June 2011

Plasma levels of total high density lipoprotein cholesterol (HDL) and its subfractions (HDL2 and HDL3) were measured in 366 healthy Caucasian males; these values were related to a number of coronary risk factors. On univariate statistical analysis, total HDL was negatively correlated with cigarette consumption, body mass index, and serum triglycerides, and positively associated with level of physical activity and alcohol consumption. HDL2 showed an inverse relationship with cigarette consumption, body mass index, triglycerides, and systolic blood pressure and a positive relationship with age. HDL3 was negatively correlated with cigarette smoking, body mass index, and triglycerides and positively associated with exercise level and alcohol consumption. Total HDL and HDL2 were inversely related to coronary risk rating, but HDL3 showed no significant correlation. Many of these relationships became nonsignificant after allowing for the effects of other variables. In particular, none of the HDL measurements correlated significantly with risk score after allowing for the effect of triglycerides. There is insufficient evidence at present to recommend the inclusion of HDL subfractions as routine screening tests for heart disease.
Accelerated rates of collagen synthesis in atherosclerotic arteries quantified in vivo.
Authors: Opsahl W P , DeLuca D J , Ehrhart L A
Published: June 2011

Rates of arterial collagen and noncollagen protein synthesis were quantified in vivo in rabbits maintained for 4 months on a control diet or the same diet supplemented with 2% peanut oil and 0.25% cholesterol. Thoracic aortas from animals fed the atherogenic diet exhibited raised lesions covering 75% to 100% of the surface. The dry delipidated weight and collagen content of these arterial segments both were significantly increased. The rates of protein synthesis were determined in rabbits given a bolus intravenous injection of 3H-L-proline (1.0 mCi/kg) and unlabelled proline (7 mmol/kg) to attain steady-state levels of specific radioactivity of free proline in plasma and tissues. Plasma proline specific activity decreased only 20% over a 5-hour period and was similar to free proline in arterial tissue, skin, and lung. Collagen synthesis rates (ng/mg dry delipidated weight per hour) were increased 10-fold in the intima plus inner media of atherosclerotic thoracic aortas compared with controls. Rates of collagen synthesis were also increased in the abdominal aortas, whereas protein synthesis in lung and skin was unaffected by diet. Increased rates of collagen synthesis in atherosclerotic arteries significantly exceeded the increases in noncollagen protein synthesis. In addition, collagen synthesis rates in vivo were 12 to 20 times greater than previously measured in vitro. These results demonstrate for the first time in vivo that collagen accumulation in the developing atherosclerotic plaque is in part due to accelerated rates of collagen synthesis by intimal smooth muscle cells.
Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. Results from the Framingham Offspring Study.
Authors: McNamara J R , Campos H , Ordovas J M , Peterson J , Wilson P W , Schaefer E J
Published: June 2011

The presence of low molecular weight low density lipoprotein (LDL) particles in plasma has been associated with premature coronary artery disease. In this study we have examined factors affecting LDL subfraction distribution as determined by 2% to 16% polyacrylamide-agarose gradient gel electrophoresis of whole plasma in a normal, primarily middle-aged, population of adult male and female participants (n = 280, ages 25 to 75 years) in the Framingham Offspring Study. Seven major LDL bands (LDL-1 to LDL-7) were observed in different individuals, with most subjects having either one or two major bands. The presence of low molecular weight LDL (LDL-4 to LDL-7) in plasma as the predominant LDL type was significantly more common in men than in women (43.5% versus 14.8%, p less than 0.001). The presence of low molecular weight LDL was correlated (p less than 0.01) with increased age, plasma triglyceride, total cholesterol, very low density lipoprotein (VLDL) cholesterol, LDL cholesterol (in women only), and apolipoprotein (apo) B concentrations, as well as with decreased high density lipoprotein (HDL) cholesterol and apo A-I levels. Approximately 69% of the variability in LDL subfractions could be accounted for by alterations in plasma triglyceride and HDL cholesterol levels. These data are consistent with the concept that LDL subfraction distribution is influenced by gender and plasma lipoprotein levels and can be determined readily by the use of whole plasma.
Substratum-bound elastin peptide inhibits aortic smooth muscle cell migration in vitro.
Authors: Ooyama T , Fukuda K , Oda H , Nakamura H , Hikita Y
Published: June 2011

Migration of smooth muscle cells (SMCs) of the media through the internal elastic lamina to the intima in response to various chemoattractants is considered to be an important event in the development of atherosclerosis. We evaluated the influence of elastin peptides prepared from normal aorta on migration of cultured rat aortic SMCs in vitro. Studies with filters coated with elastin peptides in a modified Boyden's chamber showed that the migratory response of cultured rat aortic SMCs in response to platelet-derived factors was impeded by filter-bound elastin peptides. The inhibitory effect appeared to be relatively specific for elastin peptides and for SMCs, as other matrix components (Types I, III, IV, and V collagens and fibronectin) did not impede SMC migration, and polymorphonuclear leukocytes were not impeded by elastin peptides. Elastin peptides in solution in the lower well caused the migratory response, and this response was also inhibited by filter-bound elastin peptides. Attractants such as platelet-derived factors and elastin peptides are likely to be present in the matrix around migrating SMCs. These studies suggest that elastin peptides adhering to the substratum or elastin, a major component of elastic fiber, may be one of the natural inhibitors of vascular SMC migration in response to chemoattractants in the fluid phase.
Effect of metoprolol on diet-induced atherosclerosis in rabbits.
Authors: Ostlund-Lindqvist A M , Lindqvist P , Bräutigam J , Olsson G , Bondjers G , Nordborg C
Published: June 2011

The effect of metoprolol, a beta 1-blocker, on atherogenesis was evaluated in rabbits fed a diet supplemented with 0.25% cholesterol and 3% coconut oil for 21 weeks. After 7 weeks on the diet, the rabbits were randomly divided into treated (n = 22) and untreated (n = 22) groups. Treated animals received metoprolol subcutaneously by an osmotic pump for 14 weeks, resulting in a plasma level of 774 +/- 69 nM during the investigation. Plasma concentrations of cholesterol, triglycerides, and phospholipids did not differ between the two groups. Nor were there any significant differences between the two groups in plasma concentrations of apolipoprotein A-I, apolipoprotein B, apolipoprotein C-III, and apolipoprotein E measured by electroimmunoassay. At the end of the study, the aortas were cut into three portions and the extent of atherosclerosis was determined by morphometry. The group that had received metoprolol had significantly (p less than 0.015) less atherosclerosis in the aorta (ascending plus arch 37.8 +/- 6.8%, thoracic 32.9 +/- 6.1%, abdominal 19.8 +/- 6.1% of total intimal area; mean +/- SEM) than the controls (ascending plus arch 54.9 +/- 7.1%, thoracic 48.0 +/- 6.2%, abdominal 25.9 +/- 5.5%).
Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes.
Authors: Taskinen M R , Kuusi T , Helve E , Nikkilä E A , Yki-Järvinen H
Published: June 2011

To study the effects of rigorous insulin therapy on serum lipoproteins in patients with noninsulin-dependent diabetes not controlled with oral agents only, we measured serum lipoproteins, apoproteins, lipolytic enzymes, and glucose disposal using an insulin clamp technique before and after 4 weeks of insulin therapy. Lipoproteins were isolated by ultracentrifugation and high density lipoprotein (HDL) subfractions, by rate-zonal density gradient ultracentrifugation. The group included 11 women and eight men (age 58 +/- 1 years and RBW 125 +/- 4%). Body weight, glycosylated hemoglobin, mean diurnal glucose, plasma free insulin, and glucose uptake (M-value) were 75 vs. 76 kg; 11.9 vs. 8.9%; 234 vs. 124 mg/dl; 12 vs. 27 microU/ml; and 5.0 +/- 0.4 vs. 7.1 +/- 0.6 mg/kg/min before and after insulin therapy, respectively. After insulin therapy there was a decrease of very low density lipoprotein (VLDL) triglyceride (-60%, p less than 0.001) but an increase of HDL2 cholesterol (+21%, p less than 0.001); HDL2 phospholipids (+38%, p less than 0.001); HDL2 proteins (+23%, p less than 0.01); and HDL2 mass (127 +/- 11 vs. 158 +/- 12 mg/dl, p less than 0.001). There was a decrease of HDL3 cholesterol (-13%, p less than 0.05); HDL3 phospholipids (-16%, p less than 0.05); HDL3 proteins (-18%, p less than 0.001); and HDL3 mass (179 +/- 6 vs. 146 +/- 6, p less than 0.01). Zonal profiles showed a redistribution of particles from HDL3 to HDL2. Serum apo A-I increased (p less than 0.05), apo A-II remained constant, but apo B decreased (-29%, p less than 0.001). The most marked change during insulin therapy was a 2.3-fold increase in adipose tissue lipoprotein lipase (LPL) activity (p less than 0.001). The changes of VLDL and HDL subfractions were not explained by respective changes of the blood glucose, free insulin, or M-value. The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2.
Apolipoprotein E-binding proteins isolated from dog and human liver.
Authors: Beisiegel U , Weber W , Havinga J R , Ihrke G , Hui D Y , Wernette-Hammond M E , Turck C W , Innerarity T L , Mahley R W
Published: June 2011

Chylomicron remnant catabolism appears to be mediated by apolipoprotein (apo) E binding to hepatic lipoprotein receptors. Previously, the apo B,E(LDL) receptor and a unique apo E-binding protein (referred to as the apo E receptor) were isolated from solubilized canine and human livers. In the present study, the apo E-binding fraction was further characterized and found to contain at least three proteins, all of which bind apo E-containing lipoproteins with high affinity. The 56-kDa band was found to contain the alpha- and beta-subunits of F1-ATPase, presumably derived from mitochondrial membranes. In addition, an apo E-binding protein with an apparent Mr approximately equal to 59,000 was identified. The 59-kDa protein displays calcium-independent binding on ligand blots, but displays both calcium-dependent and -independent binding in assays performed with detergent-solubilized protein. The 59-kDa protein recognized lipid-free as well as lipid-bound apo E in ligand blots, and also bound apo E-2, apo E-3, and apo E-4 in a comparable way. Monoclonal antibodies produced against the 59-kDa protein did not react with the 56-kDa proteins. Normal human liver, as well as the liver of a patient lacking the apo B,E(LDL) receptor, possessed the 56-kDa and 59-kDa proteins. These data indicate that liver cells possess at least three proteins, in addition to the apo B,E(LDL) receptor, that bind apo E-containing lipoproteins with high affinity. The physiological role of these proteins in apo E metabolism remains to be determined.
Enhanced macrophage uptake of low density lipoprotein after self-aggregation.
Authors: Khoo J C , Miller E , McLoughlin P , Steinberg D
Published: June 2011

Incubation of mouse peritoneal macrophages with native human low density lipoprotein (LDL) did not cause any significant storage of intracellular cholesteryl esters. However, when the LDL was subjected to brief (30-second) vortexing, it formed self-aggregates that were rapidly ingested and degraded by macrophages, converting them to cholesteryl ester-rich foam cells. Such aggregates were as potent as acetyl-LDL in stimulating cholesterol esterification in the macrophages. The degradation of LDL aggregates was strongly inhibited by cytochalasin B (85%), whereas degradation of native LDL was only weekly inhibited (23%), suggesting that uptake occurred by phagocytosis rather than pinocytosis. Several lines of evidence suggest that the phagocytic uptake depends, in part, upon the LDL receptor and not the acetyl-LDL receptor: 1) soluble, native LDL and beta-VLDL (but not acetyl-LDL) competed for uptake and degradation of LDL aggregates; 2) reductive methylation of LDL before vortexing reduced the effect of the aggregates on degradation and cholesterol esterification; 3) heparin, which inhibits binding of native LDL to its receptor, reduced the degradation of LDL aggregates. These studies show that self-aggregation of LDL markedly enhances its uptake by macrophages, probably by phagocytosis and at least, in part, via the LDL receptor. Aggregates of LDL in the artery wall--either self-aggregates or mixed aggregates including matrix components--may induce foam cell formation and favor the formation of the fatty streak.
Lipoprotein Lp(a). A risk factor for myocardial infarction.
Authors: Hoefler G , Harnoncourt F , Paschke E , Mirtl W , Pfeiffer K H , Kostner G M
Published: June 2011

The aim of this study was to test plasma lipoprotein Lp(a) and other lipid and lipoprotein levels for association with the incidence of myocardial infarction. Total plasma cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and Lp(a) were measured in 1486 men at the age of 18 years. In addition, the Broca Index (a measure of relative body weight) and other data were recorded. The sample was divided into probands whose mothers or fathers suffered a myocardial infarction (case group, n = 52) and into probands whose parents had no myocardial infarction (control group, n = 1434). In the case group, 32% had Lp(a) plasma concentrations greater than 25 mg/dl, but only 13.4% of the control group had this level of concentration, a highly significant difference (p less than 0.01). In addition, there was a statistically significant difference in the ratio of LDL cholesterol/HDL cholesterol (p less than 0.05) and the Broca Index (p less than 0.01) between cases and controls. The parents of the case group were significantly older than the parents of the control group; however, when a control group was matched for parents' age, the results were similar. These data suggest that parents of male children with Lp(a) plasma concentrations greater than 25 mg/dl have a 2.5-fold higher incidence of myocardial infarction. Considering the familial aggregation of elevated Lp(a) levels, we conclude that increased levels of this lipoprotein may be a significant risk factor for myocardial infarction.
Interaction of ethanol, prostacyclin, and aspirin in determining human platelet reactivity in vitro.
Authors: Jakubowski J A , Vaillancourt R , Deykin D
Published: June 2011

Ethanol partitions into cellular membranes and alters membrane-associated phenomena in numerous cell types. Since platelet aggregation and its inhibition by prostacyclin are mediated by membrane-associated receptors and enzymes, we examined the interaction of ethanol, prostacyclin, and aspirin on human platelet reactivity. Using platelet-rich plasma, we examined the effect of increasing concentrations of ethanol (0.05% to 1.0%) on the platelet-inhibitory effects of a submaximal dose (5 x 10(-10) M) of prostacyclin, the concomitant production of cyclic 3',5'-adenosine monophosphate (AMP), and the release of thromboxane A2. Ethanol alone had little effect on platelet aggregation induced by 5 micrograms/ml collagen; however, it potentiated the inhibitory effect of prostacyclin on platelet aggregation in a dose-dependent manner in the range of 0.05% to 1.0% ethanol. Whereas prostacyclin increased platelet cyclic AMP levels, ethanol had no further effect on cyclic AMP levels. Ethanol alone reduced thromboxane A2 generation, but this effect could not totally account for the observed interaction of ethanol and prostacyclin on aggregation, since aspirin did not totally abolish the interaction. The dose range in which the ethanol/prostacyclin/aspirin interactions occur encompasses the plasma levels of ethanol that may be achieved by the consumption of alcoholic beverages. The results may, in part, explain the dose-related physiological and pathological consequences of chronic alcohol consumption on the cardiovascular system.
Atherogenicity and carcinogenicity of high-arsenic artesian well water. Multiple risk factors and related malignant neoplasms of blackfoot disease.
Authors: Chen C J , Wu M M , Lee S S , Wang J D , Cheng S H , Wu H Y
Published: June 2011

The objective of this study was to examine multiple risk factors and correlated malignant neoplasms of blackfoot disease (BFD), a unique peripheral vascular disease related to continuous exposure to high-arsenic artesian well water. A total of 241 BFD cases, including 169 with spontaneous or surgical amputations of affected extremities, and 759 age-sex-residence-matched healthy community controls were studied to explore the risk factors of BFD. Multiple logistic regression analysis showed that artesian well water consumption, arsenic poisoning, familial history of BFD, and undernourishment were significantly associated with the development of BFD. The life-table method used to analyze cancer mortality of 789 BFD patients followed for 15 years showed a significantly higher mortality from cardiovascular diseases, peripheral vascular diseases, and cancers of bladder, skin, lung, and liver among BFD patients as compared with the general population in Taiwan or residents in the BFD-endemic area. The results imply the atherogenicity and carcinogenicity of the artesian well water in the BFD-endemic area.
Enhanced metabolism of normolipidemic human plasma very low density lipoprotein in cultured cells by exogenous apolipoprotein E-3.
Authors: Eisenberg S , Friedman G , Vogel T
Published: June 2011

In this investigation in cultured human fibroblasts, an attempt was made to determine the optimal metabolism of apolipoprotein (apo) B-100 lipoproteins from normolipidemic human subjects. We supplemented culture systems containing 125I-lipoproteins with exogenous recombinant or plasmatic apo E-3. Very low density lipoprotein (VLDL) fractions I, II, and III, and low density lipoproteins (LDL) were prepared from one E 4/3 and four E 3/3 subjects. Without added apo E-3, cellular metabolism (binding, cell association, and degradation) of VLDL-I, II, and III was negligible. Exogenous apo E-3 caused a many-fold enhancement of the metabolism of the three VLDL fractions, but LDL was not affected. The effects of apo E-3 were specific, not observed with apo E-2, and not observed on receptor-negative cells. Exogenous apo E-3 also enhanced down-regulation of cellular sterol synthesis by the VLDLs, but not LDL, indicating increased particle catabolism by the cells. The optimal concentrations of exogenous apo E-3 were 4 to 6 micrograms protein/15 micrograms VLDL-protein, when most of the added apo E-3 became associated with the VLDL particles. Apo E-3 failed to associate with LDL. These results demonstrate that availability and association of adequate amounts of apo E-3 are crucial for optimal cellular metabolism of apo B-100 lipoproteins along the VLDL----LDL cascade.
Interaction of native and cell-modified low density lipoprotein with collagen gel.
Authors: Hoover G A , McCormick S , Kalant N
Published: June 2011

We have examined the binding of native and cell-modified low density lipoprotein (LDL) to gels of Type I collagen. Diffusion of native 125I-LDL into the collagen gel was slow, reaching equilibrium after 24 to 48 hours, while L-3H-glucose, a low molecular weight marker, equilibrated in 6 hours. Binding of 125I-LDL was measured at 48 hours as the amount associated with the collagen after extensive washing. Binding was saturable with an increasing concentration of LDL. Prior incubation with cell-free culture medium resulted in modest, but progressive, increases in electrophoretic mobility and binding to collagen. Incubation with cells produced a marked increase in electrophoretic mobility and a 5- to 10-fold increase in collagen binding; the presence of butylated hydroxytoluene during incubation prevented both effects. These changes in LDL were induced by porcine aortic endothelial cells, smooth muscle cells, human skin fibroblasts, and a variety of cell lines, as well as by acetylation. There was a curvilinear relationship between the amount of LDL protein bound and the net negative charge of the LDL; increasing net charge was associated with progressively greater increases in binding. These results suggest a potential role for collagen in trapping lipid in the extracellular matrix of arterial intima by slowing the diffusion of and by binding LDL. The data also demonstrate that binding of LDL to collagen is enhanced by modifications that increase its net negative charge.
Quantitative ultrasound pulsation study in human carotid artery disease.
Authors: Barth J D , Blankenhorn D H , Wickham E , Lai J Y , Chin H P , Selzer R H
Published: June 2011

Pulsation in the human carotid artery during two complete cardiac cycles was studied by using computer digitized video-frames from B-mode ultrasound images. Eight patients with identifiable atherosclerotic lesions in the common carotid immediately proximal to the bulb area were studied. Diameter, strain, and elastic modulus were compared between lesion site and an adjacent reference segment 1 or 2 cm proximal to the bulb. As controls, nine patients without identifiable lesions were analyzed. The results indicate a significantly wider diameter (p less than 0.01) at the proximal reference site in patients with lesions as compared to comparable segments in control patients. The strain was significantly lower (p less than 0.05), whereas the elastic modulus was significantly higher (p less than 0.05), at the lesion site as compared to the proximal reference sites in patients with lesions. These results may indicate that an initial dilation of the carotid artery followed by loss of wall flexibility may be associated with atherosclerotic lesion formation.
Comparison of two measures of atherosclerosis in a prospective epidemiology study.
Authors: Reed D M , Strong J P , Hayashi T , Newman W P , Tracy R E , Guzman M A , Stemmermann G N
Published: June 2011

Two different methods of measuring atherosclerosis, the American Heart Association panel method and the International Atherosclerosis Project unaided visual estimation, were used to estimate the extent of atherosclerosis in the coronary arteries and aortas from 225 men who participated in a prospective study of cardiovascular disease. The two methods produced quite different results of frequency distribution of levels of atherosclerosis. The correlations of the two measures of atherosclerosis were also relatively low for both the coronary arteries (0.63) and the aortas (0.74). The correlation of atherosclerosis with major risk factors was generally higher with the unaided visual estimation method than with the panel method, except for cigarette smoking. However, the associations of coronary atherosclerosis with autopsy-documented myocardial infarction and with clinical coronary disease were similar for the two measures. Thus, it is clear that the estimate of extent of atherosclerosis and its associations with major risk factors depends upon the method used to measure atherosclerosis. Epidemiologic studies that use only one method may miss some types of risk factor associations.
Expression of apolipoprotein B epitopes in lipoproteins. Relationship to conformation and function.
Authors: Marcel Y L , Hogue M , Weech P K , Davignon J , Milne R W
Published: June 2011

The immunochemical properties of apolipoprotein (apo) B have been studied in very low density lipoprotein (VLDL)1 (Sf 100 to 400), VLDL2 (Sf 60 to 100), VLDL3 (Sf 20 to 60), different intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) subfractions isolated from patients with type IV hypertriglyceridemia. In these lipoproteins, we characterized the association of apo B with other apolipoproteins and the expression and immunoreactivity of several apo B epitopes close to the apo B receptor binding sites (3F5, 4G3, 3A8, and 5E11) and of other epitopes located on the apo B100-B48 common region (1D1 and 2D8). Immunoprecipitation showed that the proportion of lipoprotein particles expressing each apo B epitope increased from VLDL1 to LDL2; this was more apparent with 3A8 and 5E11 than with 3F5. The VLDL that were negative for apo E epitopes (60% or more of the total) were enriched in apo C. The lipoprotein particles containing apo E and/or apo C-III decreased progressively from VLDL1 (30% and 85%, respectively) to LDL2 (10% and 25%, respectively). Similar observations were made for apo C-I and apo D, demonstrating that apolipoprotein heterogeneity is greatest in the lightest lipoproteins. By competitive radioimmunoassay, the epitope for 4G3 was equally immunoreactive in each lipoprotein subclass, and the affinity constant (Ka) of 4G3 for different lipoproteins showed little variation. In contrast, both immunoreactivity and Ka of 3A8 and 5E11 increased progressively and significantly with the increasing density of the lipoprotein subclasses. This phenomenon is correlated with the increasing binding affinity of apo B in these lipoprotein subclasses to the LDL receptor of fibroblasts. We conclude that, as the apo B-containing lipoproteins become smaller, the conformation of specific regions of apo B is modified: in the receptor binding domain, the conformation of epitope 4G3, which is mapped between residues 2980 and 3080, remains constant, while that of 3A8 and 5E11 (residues 3441 to 3568) changes progressively. We propose the theory that the change in conformation in the domain spanning residues 3441 and 3568 allows the maximum expression of epitopes 3A8 and 5E11 and of the receptor binding site.
Pvu II polymorphism of low density lipoprotein receptor gene and familial hypercholesterolemia. Study of Italians.
Authors: Daga A , Fabbi M , Mattioni T , Bertolini S , Corte G
Published: June 2011

Familial hypercholesterolemia is a metabolic disorder inherited as an autosomal dominant trait characterized by an increased plasma low density lipoprotein (LDL) level. It has been demonstrated that the disease is caused by several different mutations in the LDL receptor gene. Although early identification of individuals carrying the defective gene could be useful in reducing the risk of atherosclerosis and myocardial infarction, the available techniques for determining the number of the functional LDL receptor molecules are not sufficiently accurate. The recent isolation of the LDL receptor gene now makes it possible to use restriction fragment length polymorphisms to study the inheritance of the defective allele in families with familial hypercholesterolemia. In the present study, we report the use of a Pvu II restriction fragment length polymorphism to follow the inheritance of familial hypercholesterolemia in a total of 79 patients from 37 different families. This restriction fragment length polymorphism allowed unequivocal diagnosis in 32.5% of the cases. Furthermore, in the Italians studied, the absence of a polymorphic Pvu II cutting site (P1 allele) was found to be strongly associated with familial hypercholesterolemia.
Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis. Use of monoclonal antibodies.
Authors: Bini A , Fenoglio J J , Mesa-Tejada R , Kudryk B , Kaplan K L
Published: June 2011

Samples of normal and atherosclerotic vessels obtained from vascular and cardiothoracic surgery were examined for the distribution of fibrinogen/fibrin I, fibrin II, and fibrin(ogen) degradation products (Fragment D/DD) by using recently characterized monoclonal antibodies that recognize and distinguish the three molecular forms (MAbs 18C6, T2G1, and GC4, respectively) with the ABC-immunoperoxidase technique. In normal aortas, little fibrinogen/fibrin I or fibrin II was present and no fibrin(ogen) degradation products could be detected. In early lesions and in fibrous plaques, fibrinogen/fibrin I and fibrin II were distributed in long threads and surrounding vessel wall cells and macrophages. Fibrin(ogen) degradation products were not seen in early lesions. In fibrous and advanced plaques, fibrinogen/fibrin I, fibrin II, and fibrin(ogen) degradation products were detected in areas of loose connective tissue, in thrombus, and around cholesterol crystals. The results of this study suggest that increased fibrin formation and degradation may be associated with progression of atherosclerotic disease. The observed distribution of the different molecular forms of fibrinogen also suggests the possibility that the cells present in the lesions actively participate in the fibrinogen-to-fibrin transition within the vessel wall.
Effects of chronic ethanol consumption in atherosclerosis-prone JCR:LA-corpulent rat.
Authors: Russell J C , Amy R M , Manickavel V , Dolphin P J
Published: June 2011

Rats of the atherosclerosis-prone JCR:LA-corpulent strain were subjected to long-term low (0.5% wt/vol) or high (4% wt/vol) consumption of ethanol from 1 to 12 months of age. The corpulent rats are hyperphagic, obese, and insulin-resistant; exhibit a marked very low density lipoprotein hyperlipidemia; and develop both vascular and myocardial lesions while eating a normal rat chow. The total lipid profile of the rat sera showed only limited changes with ethanol consumption. There were also no significant effects on high density lipoprotein lipids. Ethanol consumption was associated with elevated fasting glucose concentrations in both lean and corpulent rats and a strong decrease in fasting insulin levels and pancreatic B-cell volume density in the hyperinsulinemic corpulent rats. The relative frequency of myocardial nodules of chronic inflammatory cells was increased in the ethanol-consuming rats, both lean and corpulent. In contrast, old organized lesions (scars) were absent in the ethanol-consuming corpulent rats. Thus, ethanol consumption had no major effect on serum lipids or lipoproteins in the corpulent rat but was associated with a reduction in insulin resistance and islet cell hyperplasia, with an associated decreased incidence of myocardial lesions.
Hormonal contraceptive increases plasma lipid peroxides in female rats. Relationship to platelet aggregation and lipid biosynthesis.
Authors: Ciavatti M , Blache D , Renaud S
Published: June 2011

We investigated whether changes in plasma oxidative properties could occur after oral (hormonal) contraceptive (OC) administration in female rats and whether such changes could be responsible for the platelet increase in aggregation and lipid biosynthesis observed with that treatment. Platelets and plasma (platelet-poor) from control and OC (ethinyl estradiol + lynestrenol)-treated rats were prepared separately. Thrombin-induced aggregation of control platelets was markedly enhanced after incubation for 4 (p less than 0.025) to 60 (p less than 0.001) minutes in OC as compared with control plasma. Under the same conditions, platelet lipid biosynthesis was increased also (p less than 0.05 to p less than 0.01), but after 3 hours incubation. The enhanced response of platelets to aggregation induced by OC plasma could be inhibited by adding either glutathione (p less than 0.025), vitamin E (p less than 0.025), catalase (p less than 0.05), or peroxidase + glutathione (p less than 0.005) to plasma or 2,6,di-bis(ter-butyl)p-cresol (p less than 0.05) to platelets before incubation. The peroxidized free fatty acids isolated from OC plasma added to normal platelets induced a 150% (p less than 0.001) increase in the response to thrombin as compared with the fatty acids from control plasma. In addition, the level of malondialdehyde and conjugated dienes was significantly (p less than 0.02 to p less than 0.001) increased in OC compared with control plasma. We conclude that the enhanced formation in plasma of lipid hydroperoxides seems to be the initial event stimulating platelets after OC treatment, at least in rats.
Age- and sex-related differences in lipoproteins containing apoprotein A-I.
Authors: Ohta T , Hattori S , Murakami M , Nishiyama S , Matsuda I
Published: June 2011

We investigated age- and sex-related differences in the structure and composition of two species of lipoproteins that contain apoprotein (apo) A-I (A-I Lp): lipoproteins containing apo A-I and apo A-II (Lp A-I/A-II), and lipoprotein containing apo A-I but no apo A-II (Lp A-I), which were isolated by immunoaffinity chromatography. Sixty normolipidemic volunteers were assigned to one of three groups based on their ages and sexual maturation (Group A, prepubertal; Group B, puberty; and Group C, postpuberty). In A-I Lp, the levels of total cholesterol, cholesteryl ester, phospholipid, and apo A-I were lower in males during puberty and then remained stable. In Lp A-I/A-II, there were no age- or sex-related changes in lipids or in apo A-II. Levels of apo A-I in the females were lower with advance in age, although significant differences were observed only between pre- and postpubertal subjects. In Lp A-I, the levels of total cholesterol, cholesteryl ester, phospholipid, and apo A-I were lower in males during puberty and remained stable thereafter, as in the case of A-I Lp. Therefore, the age- and sex-related differences observed in A-I Lp appear to be primarily due to the differences in Lp A-I. When we take into account the constancy of Lp A-I/A-II levels in all groups, the physiological function of A-I Lp (high density lipoprotein) in each individual may be limited by the Lp A-I levels.
Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit.
Authors: Arad Y , Badimon J J , Badimon L , Hembree W C , Ginsberg H N
Published: June 2011

The concentration of dehydroepiandrosterone sulfate (DHEA-S) in human plasma is higher than any other steroid. Recent evidence has suggested an inverse relationship between plasma DHEA levels and the development of coronary atherosclerosis in humans. We used the cholesterol-fed rabbit model to investigate whether DHEA feeding would diminish aortic fatty streak formation in this model. Fifteen New Zealand White rabbits were fed rabbit chow supplemented with 0.5% cholesterol (wt/wt). Seven animals were, in addition, fed DHEA, 0.5% of diet (wt/wt). Animals were sacrificed after 2 months, and the aortic involvement with fatty streaks was evaluated by computerized planimetry of Sudan IV-stained aortas and by chemical analysis of aortic wall lipids. Compared to controls, DHEA-fed animals had similar plasma levels of total, very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, corticoids, and estrogens. DHEA-fed animals had higher plasma levels of total, VLDL, and LDL triglycerides and lower HDL triglycerides than did controls. DHEA feeding resulted in 30% and 40%, respectively, inhibition of fatty streak formation by chemical analysis and planimetry. We conclude that DHEA feeding inhibits the development of aortic fatty streaks in cholesterol-fed rabbits, independent of changes in plasma total and LDL cholesterol levels of DHEA conversion to estrogens or corticoids.
Comparison of arterial intimal clearances of LDL from diabetic and nondiabetic cholesterol-fed rabbits. Differences in intimal clearance explained by size differences.
Authors: Nordestgaard B G , Zilversmit D B
Published: June 2011

Arterial intimal clearances of low density lipoproteins (LDL) from diabetic cholesterol-fed rabbits (D-LDL) and LDL from nondiabetic cholesterol-fed rabbits (N-LDL) were compared. In six experiments, D-LDL and N-LDL were isolated from a diabetic and a nondiabetic rabbit, were iodinated with 125I and 131I, respectively, were mixed, and were reinjected into the same two rabbits as well as into a normal rabbit. Fractional catabolic rates for D-LDL and N-LDL in normal rabbits were 0.065 and 0.074 h-1 (p less than 0.05), respectively. For five of the six pairs of LDL, the D-LDL was smaller than N-LDL as determined by gel filtration. The arterial permeability to N-LDL, when normalized for differences in arterial cholesterol content, did not appear to differ between diabetic and nondiabetic rabbits. The relative arterial intimal clearance (D-LDL/N-LDL) in arteries from diabetic and nondiabetic rabbits was inversely related to the relative molecular weight (D-LDL/N-LDL). For example, when the molecular weight of D-LDL was as low as 60% of that of N-LDL (i.e., the diameter of D-LDL was reduced 16%), the intimal clearance of D-LDL was 40% larger than that of N-LDL. When, on the other hand, molecular weights and diameters of the two LDL were similar, the intimal clearance was also quite similar. These results suggest that arterial intimal clearance of LDL from diabetic and nondiabetic cholesterol-fed rabbits is comparable unless the two types of LDL have a different size.
Transendothelial transport of low density lipoprotein in association with cell mitosis in rat aorta.
Authors: Lin S J , Jan K M , Weinbaum S , Chien S
Published: June 2011

Atherosclerosis is characterized by focal areas of lipid accumulation and intimal smooth muscle cell proliferation in large arteries. In vivo studies on rat aorta with Evans blue-albumin conjugate (EBA) have shown that there are preferential sites of increased permeability with an increased uptake of the conjugate. It has been shown that these blue areas are associated with a high endothelial cell turnover rate and an enhanced permeability to lipids. In a previous study, we demonstrated that 99% of endothelial cells in the mitotic (M) phase as identified by hematoxylin staining of the dividing nuclei exhibited EBA leakage and that these dividing cells accounted for 30% of all leakage sites. In the present study, experiments were performed on the thoracic aortas of 10 adult male Sprague-Dawley rats to determine the statistical frequency of isolated leaks to Lucifer yellow-low density lipoprotein conjugate (LY-LDL) at the level of individual cells and to assess the relationship of such leaks to the cell turnover processes. Leakage of LY-LDL around individual endothelial cells was visualized by fluorescence microscopy, and cells in mitosis on the same specimens were identified by hematoxylin staining. Although endothelial cell mitosis is infrequent (0.034%), 80% of dividing cells in the M phase were associated with LY-LDL leakage. These dividing cells accounted for 45% of all leakage spots. These findings lend support to our recent hypothesis that transiently open junctions surrounding the endothelial cells undergoing cell turnover provide pathways through which LDL enters the subendothelial space, resulting in lipid accumulation.
Effect of lanthanum chloride on established atherosclerosis in the cholesterol-fed rabbit. Mitral valve as a site for assessment of treatment effects.
Authors: Gillies P J , Robinson C S , Cockrell B Y , Graepel G J
Published: June 2011

The ability of lanthanum chloride (LaCl3) to retard the progression of established atherosclerosis was investigated in cholesterol-fed rabbits. Rabbits were initially maintained on a high-fat plus cholesterol-supplemented diet for 10 weeks to induce lesions and were then changed to a low-fat diet or a low-fat diet supplemented with LaCl3 for an additional 24 weeks to permit their serum cholesterol levels to normalize. LaCl3 did not affect the rate at which serum cholesterol levels returned to normal. The dose of LaCl3 was approximately 30 mg/kg body weight/day. In comparison with controls, LaCl3-treated rabbits exhibited histologically less severe coronary artery and mitral valve atherosclerosis. Lesion severity in the carotid arteries was unaffected by LaCl3 treatment. Although statistically significant, the salutary effects of LaCl3 were relatively small. The data support the hypothesis that calcium antagonists can retard the progression of established atherosclerotic lesions. The data also illustrate the value of the mitral valve as a site to assess treatment effects on monocyte/macrophages in vivo.
Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families.
Authors: Pérusse L , Després J P , Tremblay A , Leblanc C , Talbot J , Allard C , Bouchard C
Published: June 2011

The contribution of genetic and environmental factors in serum triglycerides (TG), total cholesterol (CHOL), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and HDL-C/CHOL ratio were studied in 1630 subjects from 375 families of French descent by using a path analysis procedure. Familial correlations were computed in several pairs of biological relatives and relatives by adoption after adjustment for age and gender effects and after further adjustment for physical fitness, level of habitual physical activity, total body fat and fat distribution, diet, smoking, and alcohol consumption. The model of path analysis allowed the separation of transmissible variance (t2) into genetic (h2) and cultural (b2) components of inheritance. Under the most parsimonious solution and after adjustment for age, gender, and concomitants, the transmissible variance was entirely accounted for by genetic factors (t2 = h2), with h2 estimates of 0.52, 0.55, 0.60, and 0.63 for TG, CHOL, LDL-C, HDL-C, and HDL-C/CHOL, respectively. These estimates were similar to those obtained after adjustment for age and gender effects only. The contribution of nontransmissible environmental factors ranged from 0.48 for TG to 0.37 for HDL-C/CHOL ratio. These results suggest that both genetic and environmental factors contribute to the variation in blood lipids and lipoproteins in this population and that nongenetic influences are not associated with cultural factors transmitted across generations.
Large buoyant LDL-like particles in hepatic lipase deficiency.
Authors: Auwerx J H , Marzetta C A , Hokanson J E , Brunzell J D
Published: June 2011

Hepatic lipase (HL) is thought to play a role in processing very low density lipoprotein to low density lipoprotein (LDL). To analyze the relationship between HL and LDL, the density, size, and chemical composition of LDL isolated from 18 normal subjects and from three subjects with reduced or absent levels of HL activity were compared. In an HL-deficient subject, the major peak of apoprotein (apo) B-containing lipoproteins ('LDL') had a density of 1.023 g/ml and a diameter of 26.4 nm compared to male control subjects (1.044 +/- 0.006 g/ml and 25.3 +/- 0.3 nm). Two half-sisters of the HL-deficient subject with half the normal levels of HL activity had LDL that also were more buoyant and slightly larger than the LDL isolated from female control subjects. The peak density and average diameter of LDL were correlated with HL activity, consistent with the hypothesis that HL influenced formation and physical characteristics of typical LDL. Apo B-100 was the major apoprotein in the 'LDL' isolated from the HL-deficient subject and contained a greater proportion of triglyceride compared to the control subjects' LDL. The absence of HL appears to prevent the production of classical LDL. Our data support the hypothesis that HL helps determine normal LDL characteristics.
Factors associated with high density lipoprotein cholesterol in a population with high high density lipoprotein cholesterol levels.
Authors: Steyn K , Fourie J , Benadé A J , Rossouw J E , Langenhoven M L , Joubert G , Chalton D O
Published: June 2011

A cross-sectional study of a random sample of 976 coloureds (mixed race) of the Cape Peninsula, ages 15 to 64 years old, revealed a population with unexpectedly high levels of high density lipoprotein (HDL) cholesterol. The mean level for men was 55.4 +/- 16.1 mg/dl (SD) and for women, 60.8 +/- 16.0 mg/dl. The ratio of HDL cholesterol to total cholesterol expressed as a percentage was 26.3% +/- 9.5% for men and 28.1% +/- 9.3% for women. The HDL cholesterol levels were apparently lower than those of black and Negro populations, yet higher than those of Caucasian populations. Men with levels of HDL cholesterol above the median reported a personal history and a family history of coronary heart disease less frequently than did men with lower levels, while women with high levels of HDL cholesterol were less likely to have a history of hypertension or diabetes. Stepwise multiple regression analysis of variables significantly associated with HDL cholesterol levels showed that they explained 29.7% and 24.7%, respectively, of the variation in HDL cholesterol in men and women. Those variables independently associated with HDL cholesterol in both men and women were: serum triglyceride (-), cigarette consumption (-), alcohol, body mass index (-), age, and serum low density lipoprotein cholesterol levels (-). The reasons for the relatively high HDL cholesterol levels in this population are unknown. However, it would seem possible that these levels offer some protection against the high risk factors of smoking, hypertension, and hypercholesterolemia.
Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages.
Authors: Hoff H F , O'Neil J , Chisolm G M , Cole T B , Quehenberger O , Esterbauer H , Jürgens G
Published: June 2011

There is indirect evidence that the oxidation of low density lipoprotein (LDL) may be involved in the development of atherosclerosis. Modification of LDL by oxidation may lead to its unregulated uptake by intimal macrophages to form foam cells. Because of the complexity of events occurring during LDL oxidation, we have tested whether LDL modified directly with 4-hydroxynonenal (HNE), a major propagation product formed during lipid peroxidation and known to be present in oxidized LDL, could bring about lipid loading of macrophages. Modification was accomplished by incubating LDL with various concentrations of HNE up to 7.5 mM. When LDL was derivatized with lower concentrations of HNE, concentration-dependent increases were observed in the covalent binding of HNE to apolipoprotein B (apo B), the blockage of the epsilon-amino groups on lysine residues of apo B, and the relative electrophoretic mobility of LDL. Decreases were observed in degradation of the modified LDL by the J774 cell line, mouse peritoneal macrophages, and smooth muscle cells. Modification of LDL by incubation with the higher concentrations of HNE resulted in LDL aggregation. This modification was associated with marked increases in the macrophage degradation of LDL. Degradation of aggregated HNE-modified LDL increased linearly with incubation time, leading to lipid loading of these cells as observed by oil red O staining and cholesterol accumulation. Uptake appeared to occur by phagocytosis, since cytochalasin D, an inhibitor of phagocytosis, quantitatively inhibited uptake and degradation of labeled HNE LDL. Uptake did not appear to be mediated by either the LDL receptor or the scavenger receptor, since competition with excess amounts of LDL or acetyl LDL failed to inhibit degradation of labeled, aggregated HNE LDL. Saturation of degradation of HNE LDL by macrophages could be attributed, in part, to steric hindrance, since both excess HNE LDL and other particulate ligands could inhibit this degradation. These studies suggest that interaction of LDL with HNE formed during lipid peroxidation could be responsible for structural modifications leading to unregulated uptake of the lipoprotein by tissue macrophages. This could partially explain lipid loading or foam cell formation in atherosclerosis.