bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of computer- and human-derived coronary angiographic end-point measures for controlled therapy trials.
Authors: Mack W J , Selzer R H , Pogoda J M , Lee P L , Shircore A M , Azen S P , Blankenhorn D H
Published: June 2011

The Cholesterol Lowering Atherosclerosis Study, a randomized angiographic clinical trial, demonstrated the beneficial effect of niacin/colestipol plus diet therapy on coronary atherosclerosis. Outcome was determined by panel-based estimates (viewed in both still and cine modes) of percent stenosis severity and change in native artery and bypass graft lesions. Computer-based quantitative coronary angiography (QCA) was also used to measure lesion and bypass graft stenosis severity and change in individual frames closely matched in orientation, opacification, and cardiac phase. Both methods jointly evaluated 350 nonoccluded lesions. The correlation between QCA and panel estimates of lesion size was 0.70 (p less than 0.0001) and for change in lesion size was 0.28 (p = 0.002). Agreement between the two methods in classifying lesion changes (i.e., regression, unchanged, or progression) occurred for 60% (210 of 350) of the lesions kappa +/- SEM = 0.20 +/- 0.05, p less than 0.001). The panel identified 442 nonoccluded lesions for which QCA stenosis measurements could not be obtained. Lesions not measurable by QCA included those with stenosis greater than 85% that could not be reliably edge tracked, segments with diffuse or ecstatic disease that had no reliable reference diameter, and segments for which matched frames could not be located. Seventy-nine lesions, the majority between 21% and 40% stenosis, were identified and measured by QCA but were not identified by the panel. This comparison study demonstrates the need to consider available angiographic measurement methods in relation to the goals of their use.
Relation between insulinemia, body mass index, and lipoprotein composition in healthy, nondiabetic men and women.
Authors: Winocour P H , Kaluvya S , Ramaiya K , Brown L , Millar J P , Farrer M , Neil H A , Laker M F , Alberti K G
Published: June 2011

Altered lipoprotein composition may be a better predictor of cardiovascular disease than modestly increased serum lipid concentrations, although possible interactions between lipoprotein composition, obesity, and insulinemia have not been fully elucidated. Therefore, we investigated the association between different measures of insulinemia and lipoproteins in 297 healthy Caucasian men (body mass index [BMI] less than 27 in 233, greater than 27 [obese] in 64) and 295 healthy Caucasian women (BMI less than 25 in 198, greater than 25 [obese] in 97). Associations observed in both obese and nonobese men and women were between increasing tertiles of most insulin measures and serum triglyceride concentrations (p = 0.079-0.004) and the ratio of low density lipoprotein to high density lipoprotein cholesterol (p = 0.094-0.008). Graded reductions in the high density lipoprotein cholesterol to apolipoprotein A-I ratio were also recorded in obese women, with increasing tertiles of fasting (p = 0.014-0.007) and postglucose load (p = 0.001) serum insulin levels, after correcting for BMI and triglyceride concentrations. Less marked graded increases in the triglyceride to apolipoprotein B ratios were recorded in obese women with increasing tertiles of fasting (p = 0.001-0.006) and postglucose challenge (p = 0.081) insulinemic measures. In men with normal or slightly elevated cholesterol levels (fasting serum cholesterol less than 6.5 mmol/l), hyperapobetalipoproteinemia was recorded with increasing tertiles of insulinemia (p = 0.006, correcting for BMI and triglyceride concentrations), as well as in subjects with hypertriglyceridemia (fasting serum triglycerides greater than 1.70 mmol/l) (p = 0.004, correcting for BMI and age). Hyperinsulinemia and insulin resistance are associated with altered lipoprotein composition in obese women, presumably reflecting a complex interplay between sex hormones, body mass, and insulin action. Insulin resistance appears to be more associated with apolipoprotein B concentrations in men. The hyperinsulinemic nondiabetic subject may be at increased risk of cardiovascular disease because of altered concentrations of apolipoprotein concentrations and lipoprotein composition.
Acute in vitro effects of ethanol on responses of platelets from cholesterol-fed and Watanabe heritable hyperlipidemic rabbits.
Authors: Rand M L , Gross P L , Barrow D V , Packham M A
Published: June 2011

The effects of ethanol on platelets from rabbits with two different types of hypercholesterolemia, diet-induced and genetically determined, were investigated. There were no differences between the hypercholesterolemic groups and their controls in the extent of (primary) ADP-induced aggregation of washed platelets, and this aggregation was not inhibited by ethanol. Platelets from cholesterol-fed rabbits were more sensitive to aggregation and secretion induced by collagen, whereas platelets from Watanabe heritable hyperlipidemic (WHHL) rabbits were less sensitive. Ethanol inhibited collagen-induced responses of platelets from both hypercholesterolemic groups, but the extent of inhibition of aggregation was not different compared with controls. Because ethanol did not affect U46619-induced responses of aspirin-treated platelets, ethanol does not inhibit aggregation and secretion stimulated by collagen via an effect on thromboxane A2 (TxA2)-induced responses. Platelets from cholesterol-fed rabbits were more sensitive to thrombin even when TxA2 formation was blocked by aspirin, and inhibition of aggregation by ethanol was less in cholesterol-fed rabbits than in controls. However, neither the extent of thrombin-induced responses nor the inhibitory effect of ethanol was different in platelets from WHHL rabbits compared with controls. Thus, different etiologies of hypercholesterolemia produce different changes in platelet function, and ethanol has different effects on the platelets from cholesterol-fed rabbits compared with the platelets from WHHL rabbits. The inhibitory effect of ethanol on the thrombin-induced aggregation of platelets from cholesterol-fed rabbits is attenuated compared with controls, and this finding contrasts with the reported greater inhibitory effect of ethanol on platelets enriched with saturated fats.
Involvement of the macrophage low density lipoprotein receptor-binding domains in the uptake of oxidized low density lipoprotein.
Authors: Keidar S , Brook G J , Rosenblat M , Fuhrman B , Dankner G , Aviram M
Published: June 2011

Macrophages, unlike most other cells, possess both low density lipoprotein (LDL) and scavenger receptors. The scavenger receptor has been shown to mediate the uptake of oxidized LDL (ox-LDL), which ultimately leads to cholesterol loading of the macrophages. The present study was undertaken to define epitopes on ox-LDL that are important for lipoprotein binding to macrophages and to ascertain whether ox-LDL can bind to the LDL receptor. Monoclonal antibodies (Mabs) directed against several epitopes along the apolipoprotein B-100 (apo B-100) molecule were used. LDL (300 micrograms/ml) was oxidized by incubation with 10 microM CuSO4 for 24 hours. Ox-LDL, as opposed to acetylated LDL (ac-LDL), reacted with Mabs directed against the LDL receptor-binding domains (Mabs B1B6 and B1B3). Similarly, uptake of ox-LDL but not ac-LDL by a murine J774 macrophage-like cell line was inhibited by as much as 40% after using Mab B1B6. The anti-LDL receptor antibody IgG-C7 also inhibited 125I-ox-LDL uptake by macrophages by 60%. Chromatography on heparin-Sepharose columns of LDL that was partially oxidized for only 3 hours resulted in two fractions: an unbound fraction with characteristics similar to those of ox-LDL and a bound fraction similar to native LDL. Macrophage degradation of the unbound fraction was inhibited by Mab IgG-C7 and Mab B1B6, which are directed toward the LDL receptor and the LDL receptor-binding domains on apo B-100, respectively. When incubated with three types of macrophages, J774 macrophage cells, mouse peritoneal macrophages, and human monocyte-derived macrophages, excess amounts of unlabeled ox-LDL, like native LDL but unlike ac-LDL, substantially suppressed the uptake and degradation of 125I-labeled LDL. Similar studies with fibroblasts, however, revealed that unlabeled LDL but not unlabeled ox-LDL or ac-LDL competed with 125I-LDL for cellular uptake and degradation. Mab directed against epitopes on the amino terminus domain of apo B-100 (C14) demonstrates a similar immunoreactivity with ox-LDL and native LDL but a much lower reactivity with ac-LDL. Mab C14 inhibited macrophage degradation of ox-LDL by 34% but had no inhibitory effect on the uptake of native LDL or ac-LDL. Thus, the ac-LDL and LDL receptor-binding domains as well as a unique epitope on the amino terminus of apo B-100 may be involved in macrophage binding of ox-LDL.(ABSTRACT TRUNCATED AT 400 WORDS)
Difference in dilatation between endothelium-preserved and -desquamated segments in the flow-loaded rat common carotid artery.
Authors: Tohda K , Masuda H , Kawamura K , Shozawa T
Published: June 2011

To study arterial dilatation in response to increased flow, we observed the bilateral common carotid arteries (CCAs) of 10 16-week-old rats that were maintained for 8 weeks after construction of an arteriovenous (AV) fistula between the left CCA and the jugular vein at a level 20 mm distal from the aortic orifice. The flow in the left CCA increased 11-fold and that of the right CCA increased twofold compared with values before surgery. The left CCA showed complete desquamation of endothelial cells in the distal one third of the segment proximal to the AV fistula. In the left CCA the endothelium-preserved area dilated significantly (the luminal radius was 1.34 times larger than control; p less than 0.001, n = 4) with a significant increase of the cross-sectional area of the media (p less than 0.01, n = 4) and showed high wall shear stress (70 +/- 11 dynes/cm2 near the aortic orifice). In contrast, the endothelial cell-desquamated area did not dilate but did show very high wall shear stress (231 +/- 23 dynes/cm2) without any intimal smooth muscle cell proliferation. The right CCA dilated significantly (luminal radius was 1.07 times larger than control; p less than 0.001, n = 4) with a wall shear stress of 30 dynes/cm2 near the brachiocephalic orifice. All CCAs retained their fundamental arterial structure. We conclude that in the rat CCA, arterial dilatation in response to increased flow is a gradual remodeling process related to the presence of endothelial cells that have been influenced by the level of flow increase.
Blood velocity profiles in the origin of the canine renal artery and their relevance in the localization and development of atherosclerosis.
Authors: Yamamoto T , Tanaka H , Jones C J , Lever M J , Parker K H , Kimura A , Hiramatsu O , Ogasawara Y , Tsujioka K , Caro C C
Published: June 2011

Using a 20-MHz 80-channel pulsed Doppler velocimeter and 30-MHz high-resolution echo ultrasound, we investigated the in vivo hemodynamics at the origin of the renal artery by measuring the velocity profiles and bifurcation geometry of a surgically exposed left renal artery in 10 anesthetized dogs. The angle between the aorta and the renal artery ranged from 60 degrees to 90 degrees (mean, 84 degrees) although the bifurcation did not lie in a single anterodorsal plane and the diameter of the renal artery ranged from 1.5 to 3.5 mm (mean, 2.4 mm). Despite different geometries, the velocity profiles in the different aortorenal bifurcations were similar. Although regions of reverse velocity were observed, the net flow in the renal artery was in the forward direction throughout the cardiac cycle. The peak Reynolds' number was 486 +/- 63. The velocity profiles in the proximal renal artery in the plane parallel to the bifurcation showed velocity vectors directed toward the caudal wall throughout the cardiac cycle. Reverse flow, indicating flow separation, was observed near the cranial wall even during systole. When the probe was placed on the cranial wall perpendicular to the wall, a velocity component from the cranial side to the caudal side was observed. At a distance of four diameters from the renal ostia, velocity profiles were almost parabolic. These results indicate that the velocity pattern near the cranial wall at the renal ostia, at which atherosclerotic lesions are prone to develop, are characterized by 1) a low time-averaged shear rate, 2) separation of the flow, and 3) a time-varying oscillation of the flow.
Prostacyclin analogues inhibit tissue factor expression in the human monocytic cell line THP-1 via a cyclic AMP-dependent mechanism.
Authors: Crutchley D J , Solomon D E , Conanan L B
Published: June 2011

Increased expression of tissue factor procoagulant by peripheral blood monocytes has been implicated in a number of thrombotic disorders. The present studies were undertaken to determine whether stable analogues of prostacyclin, a potent endothelium-derived platelet inhibitor and vasodilator, could inhibit tissue factor expression by human monocytic cells. Exposure of monocytic tumor THP-1 cells to 100 ng/ml endotoxin, 2 units/ml interleukin-1 beta, or 5 ng/ml tumor necrosis factor-alpha for 4 hours led to increased tissue factor procoagulant activity. Preincubation for 30 minutes with iloprost, ciprostene, and carbacyclin led to a dose-dependent inhibition of tissue factor expression induced by all three challenging agents. Iloprost was the most potent: 50% inhibition occurred at 5 nM, a concentration close to the reported dissociation constant for iloprost binding to the platelet prostacyclin receptor. An orally active analogue, cicaprost, was equally effective against endotoxin-induced tissue factor expression. Carbacyclin and ciprostene were 100 times less potent. Iloprost prevented the endotoxin-induced expression of tissue factor antigen on the surface of THP-1 cells, as determined by flow cytometry. Iloprost (500 pM-50 nM) increased intracellular levels of cyclic AMP. This effect was potentiated by isobutylmethylxanthine, an inhibitor of phosphodiesterase. The inhibitory effects of iloprost on tissue factor expression were also potentiated by isobutylmethylxanthine and mimicked by forskolin and dibutyryl cyclic AMP but not dibutyryl cyclic GMP. These results suggest that prostacyclin may play a role in downregulating tissue factor expression in monocytes, at least in part via elevation of intracellular levels of cyclic AMP.
Mechanisms controlling competence gene expression in murine fibroblasts stimulated with minimally modified LDL.
Authors: Bork R W , Svenson K L , Mehrabian M , Lusis A J , Fogelman A M , Edwards P A
Published: June 2011

Mildly oxidized low density lipoprotein (minimally modified low density lipoprotein [MM-LDL] is capable of inducing gene expression in cells of the artery wall. In this study, we investigated the mechanisms that control the mRNA expression of JE, KC, c-myc, and c-fos in quiescent mouse L-cell fibroblasts stimulated with MM-LDL. The data demonstrate that MM-LDL induces increases greater than or equal to 20-fold in the levels of transcripts of these genes within 15-60 minutes. Of the four genes examined, JE and KC mRNA showed the greatest response to MM-LDL. The pattern of induction by MM-LDL is distinct from that observed in fibroblasts stimulated with serum, a known inducer of these genes. Treatment with cycloheximide (10 micrograms/ml) did not block the MM-LDL-induced increase in the mRNA levels of these genes. The increase of JE and KC mRNA levels in response to MM-LDL could be blocked by treatment with actinomycin D (5 micrograms/ml). In nuclear runoff studies, MM-LDL increased the transcription rate of JE and KC at 4 hours by 13-fold and fivefold, respectively. Small but reproducible stimulations of c-fos and c-myc transcription by MM-LDL were also observed. In addition, the half-life of JE mRNA was increased after addition of MM-LDL to fibroblasts, suggesting that the MM-LDL-induced accumulation of these mRNAs might be accomplished by both transcriptional and posttranscriptional mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials.
Authors: Mensink R P , Katan M B
Published: June 2011

To calculate the effect of changes in carbohydrate and fatty acid intake on serum lipid and lipoprotein levels, we reviewed 27 controlled trials published between 1970 and 1991 that met specific inclusion criteria. These studies yielded 65 data points, which were analyzed by multiple regression analysis using isocaloric exchanges of saturated (sat), monounsaturated (mono), and polyunsaturated (poly) fatty acids versus carbohydrates (carb) as the independent variables. For high density lipoprotein (HDL) we found the following equation: delta HDL cholesterol (mmol/l) = 0.012 x (carb----sat) + 0.009 x (carb----mono) + 0.007 x (carb---- poly) or, in milligrams per deciliter, 0.47 x (carb----sat) + 0.34 x (carb----mono) + 0.28 x (carb----poly). Expressions in parentheses denote the percentage of daily energy intake from carbohydrates that is replaced by saturated, cis-monounsaturated, or polyunsaturated fatty acids. All fatty acids elevated HDL cholesterol when substituted for carbohydrates, but the effect diminished with increasing unsaturation of the fatty acids. For low density lipoprotein (LDL) the equation was delta LDL cholesterol (mmol/l) = 0.033 x (carb----sat) - 0.006 x (carb----mono) - 0.014 x (carb----poly) or, in milligrams per deciliter, 1.28 x (carb----sat) - 0.24 x (carb----mono) - 0.55 x (carb---- poly). The coefficient for polyunsaturates was significantly different from zero, but that for monounsaturates was not. For triglycerides the equation was delta triglycerides (mmol/l) = -0.025 x (carb----sat) - 0.022 x (carb----mono) - 0.028 x (carb---- poly) or, in milligrams per deciliter, -2.22 x (carb----sat) - 1.99 x (carb----mono) - 2.47 x (carb----poly).(ABSTRACT TRUNCATED AT 250 WORDS)
Flow affects development of intimal hyperplasia after arterial injury in rats.
Authors: Kohler T R , Jawien A
Published: June 2011

This study examined the effects of blood flow on intimal hyperplasia after balloon catheter injury of the rat common carotid artery. Flow was altered by ligation of the opposite common carotid artery (increased flow) or of the ipsilateral internal carotid artery (decreased flow). Blood flow decreased by 35% in the low-flow group and increased by 29% in the high-flow group. Similar changes in mean velocity were observed. Cross-sectional intimal area was significantly greater in the low- than the high-flow group at 2 weeks (0.11 +/- 0.01 versus 0.06 +/- 0.01 mm2, p less than 0.01) and 4 weeks (0.17 +/- 0.02 versus 0.12 +/- 0.01 mm2, p = 0.01) but not at 1 or 8 weeks. Smooth muscle cell proliferation rates (thymidine labeling indexes) were not different in high- and low-flow groups at 2 days and at 1 and 4 weeks. Matrix accumulation at 2 and 4 weeks was the same in both groups. Mature neointima did not respond to changes in flow; when vessel ligation was delayed until 2 months after injury, there was no effect on neointimal area. These data indicate that early neointimal hyperplasia is increased when flow is reduced, possibly because of alteration of smooth muscle cell migration.
Interaction between a polymorphism of the apo A-I promoter region and smoking determines plasma levels of HDL and apo A-I.
Authors: Sigurdsson G , Gudnason V , Sigurdsson G , Humphries S E
Published: June 2011

Epidemiological studies have demonstrated that the risk of coronary artery disease (CAD) is increased in smokers but reduced in individuals with elevated plasma levels of high density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) A-I. In a sample of 315 men and women from Iceland, the mean levels of HDL-C and apo A-I in smokers were, respectively, 12% and 6% lower in men and 7% and 6% lower in women compared with nonsmokers. In the men who were nonsmokers, a guanine (G) to adenine (A) (G/A) substitution 75 bp upstream from the start of transcription of the apo A-I gene was associated with elevated levels of HDL-C and apo A-I, with those carrying the A allele having levels of HDL-C and apo A-I roughly 10% higher than those with only the G allele. This genotype effect was abolished in the men who smoked and absent in the sample of women. Based on the reported protective effect associated with elevated levels of apo A-I and HDL-C, men carrying the A allele would have roughly a 20% lower relative risk of CAD compared with those without the A allele, but only if they remained nonsmokers. This gene polymorphism would therefore be an important factor in determining those men who would most benefit from avoidance or cessation of smoking. Determining the mechanism of such interaction between genotype and environment will be important in understanding the etiology of CAD.
The effect of interferon on the metabolism of LDLs.
Authors: Schectman G , Kaul S , Mueller R A , Borden E C , Kissebah A H
Published: June 2011

Interferons have been shown to lower low density lipoprotein (LDL) cholesterol concentrations by 20-50%. To evaluate the effect of interferons on LDL metabolic behavior in individuals with normal and mildly elevated LDL cholesterol levels, autologous LDL labeled with 125I was administered to subjects at baseline and during interferon treatment. Interferon beta serine (IFN-beta serine) was administered intravenously at 4.5 x 10(6) units daily for at least 3 weeks before the start of kinetic study and continued for an additional 2 weeks. Results were analyzed by using a multicompartmental model that allows for two intravascular LDL compartments. In normal subjects, IFN-beta serine reduced LDL cholesterol and apolipoprotein (apo) B levels by 25% and 27%, respectively (p less than 0.05); LDL apo B synthesis was decreased by 59% (p less than 0.05). In hypercholesterolemic subjects, IFN-beta serine reduced LDL cholesterol levels by 38% (p less than 0.05); however, apo B concentrations and production rates were not significantly decreased. Clearance of LDL from the first intravascular apo B pool was markedly reduced in these subjects, resulting in a shift in the distribution of LDL apo B from the second to the first intravascular LDL apo B pool. We conclude that interferon's actions on LDL metabolism differ in normocholesterolemic and hypercholesterolemic subjects. In normal subjects, interferon decreased LDL cholesterol and apo B levels through a reduction in the LDL apo B production rate. However, in hypercholesterolemic subjects, interferon reduced LDL cholesterol by altering the distribution of apo B mass between LDL subspecies.
HDLs and alimentary lipemia. Studies in men with previous myocardial infarction at a young age.
Authors: Karpe F , Bard J M , Steiner G , Carlson L A , Fruchart J C , Hamsten A
Published: June 2011

The plasma concentration, particle size, and chemical composition of high density lipoproteins (HDLs) are associated with the metabolism of triglyceride-rich lipoproteins (TGRLs). During alimentary lipemia there is active exchange of lipids and apolipoproteins between HDL and apolipoprotein B-containing lipoproteins. Whereas HDL has been assigned a protective role against the development of atherosclerosis, alimentary lipemia has been proposed to represent a potentially atherogenic state. We examined plasma HDL concentration, particle size, and composition and their relations to postprandial TGRLs in 32 postinfarction patients and 10 healthy control subjects after intake of a standardized oral fat load of a mixed-meal type. All patients had undergone coronary angiographies in connection with the myocardial infarction and around 5 years thereafter. The plasma HDL cholesterol concentration decreased significantly in response to the oral fat load, particularly in hypertriglyceridemic patients, with a concomitant increase of HDL triglycerides. A limited and reversible yet consistent increase of HDL particle size (1-2%) was seen 6 hours after intake of the oral fat load on nondenaturing gradient gel electrophoresis (GGE) in both patients and control subjects. Virtually no changes in the plasma concentration of HDL GGE subclasses, lipoproteins containing apolipoprotein A-I but no apolipoprotein A-II (LpA-I), or lipoproteins containing both apolipoproteins A-I and A-II (LpA-I:A-II) were induced in the postprandial state despite massive increases of large very low density lipoprotein (VLDL) and large chylomicron remnant levels (determined as apolipoproteins B-100 and B-48 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis). Strong inverse correlations with fasting plasma HDL cholesterol and the larger HDL GGE subspecies were found for large postprandial VLDL and large chylomicron remnants, whereas the corresponding relations for small VLDL and small chylomicron remnants were weaker. The relations of both large and small VLDL and chylomicron remnants to HDL cholesterol were confined to subjects in the lower fasting plasma HDL cholesterol range (< 1.2 mmol/l). None of the HDL parameters measured, either in the fasting or in the postprandial state (HDL cholesterol, HDL triglycerides, HDL GGE subclasses, LpA-I, and LpA-I:A-II), were related to the development of coronary atherosclerosis, whereas the postprandial plasma levels of small chylomicron remnants, which showed weak negative correlations with HDL, related positively to the progression of coronary atherosclerosis.(ABSTRACT TRUNCATED AT 400 WORDS)
Identification of recurrent and novel mutations in exon 4 of the LDL receptor gene in patients with familial hypercholesterolemia in the United Kingdom.
Authors: Gudnason V , King-Underwood L , Seed M , Sun X M , Soutar A K , Humphries S E
Published: June 2011

A group of 200 patients with familial hypercholesterolemia (FH) who were attending lipid clinics in the London area have been screened for four known point mutations and a microdeletion in exon 4 of the low density lipoprotein receptor gene by polymerase chain reaction (PCR) amplification of genomic DNA and either enzyme digestion of the product or hybridization with allele-specific oligonucleotides. A point mutation of Ser156-->Leu that was initially described in a Puerto Rican family was found in one patient of Polish origin on a different haplotype from that described originally and thus is likely to have occurred independently. A 3-bp deletion that causes deletion of amino acid Gly197 was found in six of the patients, who were all of Jewish origin and who shared the same haplotype for the mutant allele. A mutation of Asp206-->Glu that has been described in the Afrikaner population was found in three patients, two of UK origin and one a recent immigrant from South Africa. In all cases the haplotype of the mutant allele was compatible with that described in the original patient. The mutations at Asp154 reported in South African patients and at Glu207 reported in French Canadian patients were not detected in this sample. However, two additional mutations have been identified in this sample: the first, a 2-bp deletion in codon 206 that was found in five patients, all of British ancestry, and the second, a point mutation in a single patient of Irish origin that creates a stop codon at residue Cys210.(ABSTRACT TRUNCATED AT 250 WORDS)
Dietary fat saturation modifies the metabolism of LDL subfractions in guinea pigs.
Authors: Fernandez M L , Abdel-Fattah G , McNamara D J
Published: June 2011

The effects of dietary fat saturation on the metabolism of low-density lipoprotein (LDL) subfractions were measured in adult male guinea pigs fed semipurified diets containing 15% (wt/wt) corn oil (CO; 58% linoleic acid), lard (24% palmitic/14% stearic acid), or palm kernel oil (PK; 52% lauric/18% myristic acid). Animals fed the CO diet had lower plasma total cholesterol levels than guinea pigs fed the PK or lard diets (P < .01). Plasma LDL-1 (d = 1.019 to 1.05 g/mL) concentrations were 3.5- and 2.4-fold higher in animals fed the PK diet compared with the CO and lard groups, respectively, while LDL-2 (d = 1.05 to 1.09 g/mL) concentrations were not different among groups. For all dietary fat groups LDL-1 had a higher molecular weight and a larger diameter than LDL-2. LDL fractional catabolic rates (FCRs) varied, depending on both the diet and the LDL subfraction. Animals fed the polyunsaturated CO diet had a more rapid LDL FCR than animals from the other two groups (P < .01). Within the same diet group, LDL-2 exhibited a slower turnover rate than LDL-1 in animals fed the PK diet, while no differences in LDL subfraction FCR were found in the CO and lard groups. Animals fed the PK and lard diets did not exhibit significant modifications in the density distribution of LDL subfractions over a period of 33 hours. In contrast, animals fed the CO diet exhibited a shift of more buoyant to denser LDL particles, suggesting that differences in LDL intravascular processing are mediated by dietary fat saturation. In vitro LDL binding to hepatic membranes confirmed the in vivo data with an increased expression of apolipoprotein B/E receptors (Bmax) in animals fed the CO diet (P < .01). Hepatic apolipoprotein B/E receptors exhibited less affinity for LDL-2 in the PK group, a result consistent with the less rapid turnover of LDL-2 in PK-fed animals. The results suggest that dietary fatty acids varying in saturation and composition have distinctive atherogenic potentials. The lowest plasma LDL cholesterol concentrations mediated by CO intake could in part be explained by induced changes in the composition and processing of LDL subfractions, resulting in faster LDL turnover rates in addition to increased expression of hepatic apolipoprotein B/E receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
Differential effects of body fatness and body fat distribution on risk factor for cardiovascular disease in women. Impact of weight loss.
Authors: Dennis K E , Goldberg A P
Published: June 2011

This study examines the role of obesity and body fat distribution (ie, waist-to-hip ratio [WHR]) on cardiovascular disease (CVD) risk factors in 50 nondiabetic, obese (body mass index [BMI], 31 +/- 2 kg/m2, mean +/- SD), 45 +/- 10-year-old women. The data obtained at baseline and after weight loss were analyzed after dividing subjects by WHR into upper-body (WHR > 0.80) and lower-body (WHR < or = 0.80) groups and by median-split BMI into more obese (BMI > or = 31) and less obese (BMI < 31) groups. At baseline, the upper-body obese women, when compared with lower-body obese women, had higher plasma triglycerides (TGs) (175 +/- 85 versus 111 +/- 47 mg/dL, respectively; P < .001) and lower high-density lipoprotein cholesterol (HDL-C) (44 +/- 10 versus 54 +/- 11, respectively; P < .01) but similar total and low-density lipoprotein cholesterol levels and blood pressure. There were no significant differences in these CVD risk factors at baseline by BMI split. Although weight loss (-9 +/- 5 kg) lowered blood pressure and TGs irrespective of WHR or BMI, only upper-body obese women raised HDL-C. Moreover, the magnitude of the changes was greatest in women with an upper-body fat distribution. In women with WHR > 0.80, HDL-C increased by 11%, to 49 mg/dL (P < .001), and TGs decreased by 24%, to 134 mg/dL (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Aortic smooth muscle cells in a three-dimensional collagen lattice culture. Evidence for posttranslational regulation of collagen synthesis.
Authors: Redecker-Beuke B , Thie M , Rauterberg J , Robenek H
Published: June 2011

Aortic smooth muscle cells were cultivated as monolayers on plastic or within collagen lattices with low- and high-serum supplementation, and the expression of mRNAs specific for pro alpha 1 (I) and pro alpha 1 (III) collagen were studied by slot blot hybridization. The steady-state levels of pro alpha 1 (I) and pro alpha 1 (III) collagen mRNA of cells within collagen lattices were found to be higher than those grown on plastic, although the production of collagen was lower. The degradation of pro alpha 1 (I) and pro alpha 1 (III) collagen mRNAs as revealed in the presence of actinomycin D was not affected by culturing the cells within a collagen lattice. In vitro translation assays of mRNAs of monolayer- and lattice-cultured cells showed no differences in translatability. These data suggest the involvement of posttranslational control of collagen production in collagen lattice-cultured smooth muscle cells.
Recombinant leech antiplatelet protein prevents collagen-mediated platelet aggregation but not collagen graft thrombosis in baboons.
Authors: Schaffer L W , Davidson J T , Siegl P K , Gould R J , Nutt R F , Brady S F , Connolly T M
Published: June 2011

Leech antiplatelet protein (LAPP) is a specific inhibitor of collagen-induced human platelet aggregation and adhesion to collagen under static conditions. Recombinant LAPP (rLAPP) and L-366,763 (acetylated-Cys-Asn-Pro-Arg-Gly-Asp-Cys-NH2), a peptidyl fibrinogen receptor antagonist, were evaluated in an anesthetized baboon thrombosis model using a collagen-coated graft segment of an arteriovenous shunt to elicit thrombus formation. Animals were randomized to receive systemic intravenous administration of rLAPP (100 micrograms.kg-1 x min-1; n = 5), L-366,763 (8.5 micrograms.kg-1 x min-1; n = 3), or saline (n = 3). Despite complete and selective inhibition of type I collagen-induced ex vivo aggregation of platelets, rLAPP had no significant effect on the rate or the extent of 111-In-labeled platelet deposition onto the collagen graft and no effect on template bleeding time. In contrast, L-366,763 completely prevented platelet deposition, maintained blood flow, and significantly prolonged bleeding time at the dosage that inhibited ex vivo aggregation in response to all agonists studied. In this study, the absence of an antithrombotic benefit of rLAPP contrasted sharply with the efficacy of the fibrinogen receptor antagonist. These results demonstrate that specific inhibition of collagen-mediated platelet aggregation alone is not sufficient to prevent platelet-dependent thrombosis in this baboon model.
LDL size and subclass pattern in a biethnic population.
Authors: Haffner S M , Mykkänen L , Valdez R A , Paidi M , Stern M P , Howard B V
Published: June 2011

Recently, the presence of small, dense low-density lipoprotein (LDL) has been recognized as a risk factor for coronary heart disease. There has been little work on correlates of LDL size in population-based studies and none in Mexican Americans. We examined the relationship of LDL size and pattern to anthropometric and metabolic variables in 466 Mexican Americans and non-Hispanic whites in the San Antonio Heart Study. LDL size in Angstrom units was significantly lower in Mexican Americans (255.8 +/- 0.6) than in non-Hispanic whites (257.9 +/- 0.7) (P = 0.041) after adjustment for gender and age. The percentage of subjects with pattern B tended to be higher in Mexican Americans than in non-Hispanic whites (40.0% versus 34.4%, respectively), although this difference did not reach statistical significance. In univariate analysis, LDL size was significantly associated with glucose (r = -.20), insulin (r = -.19), male gender (r = -.20), total cholesterol (r = -.22), high-density lipoprotein cholesterol (HDL-C) (r = .53), and triglyceride concentrations (r = -.63). In multivariate analyses, higher triglyceride, insulin, and glucose concentrations, lower HDL-C, and male gender were independent correlates of smaller, denser LDL. Correlates of LDL size were similar in Mexican Americans and non-Hispanic whites. Our results confirm previous reports that triglyceride and HDL-C concentrations are the most important variables associated with LDL size. The additional findings of independent effects of male gender, glucose, and insulin concentrations suggest that sex hormones and the insulin resistance syndrome may also play an important role.(ABSTRACT TRUNCATED AT 250 WORDS)
Oral contraceptives decrease hepatic cholesterol independent of the LDL receptor in nonhuman primates.
Authors: Colvin P L , Wagner J D , Heuser M D , Sorci-Thomas M G
Published: June 2011

Pharmacological doses of estrogens have been reported to increase hepatic catabolism of low-density lipoprotein (LDL) by the LDL receptor (LDL-R) pathway and to increase the concentration of mRNA for the LDL receptor. The induction of LDL-Rs by large doses of estrogen may not be relevant to the role of estrogens under physiological conditions. Furthermore, the mechanisms by which oral contraceptives, a combination of synthetic estrogen and progestin, may modulate LDL metabolism remain largely unexplored. Adult female cynomolgus monkeys were given combination ethinyl estradiol/norgestrel preparations (n = 16) for 16 weeks and were compared with a control group that did not receive exogenous sex hormones (n = 7). All animals consumed a diet containing 0.25 mg cholesterol/kcal with 40% of calories from saturated fats. After 16 weeks of treatment there was no significant difference in LDL cholesterol (LDL-C) and hepatic LDL-R mRNA concentration between oral contraceptive-treated animals (LDL-C, 242 +/- 113 mg/dL; LDL-R mRNA, 0.60 +/- 0.31 pg/microgram RNA) and control animals (LDL-C, 277 +/- 100 mg/dL; LDL-R mRNA, 0.51 +/- 0.21 pg/microgram RNA). In contrast, the hepatic cholesteryl ester concentration was significantly lower in the oral contraceptive-treated animals (7.28 +/- 3.59 mg/g liver) compared with the control animals (16.07 +/- 11.86 mg/g liver; P = .01) with no significant difference in hepatic free cholesterol concentration between the groups. Thus, oral contraceptives decrease hepatic cholesterol concentration independent of LDL-R expression.(ABSTRACT TRUNCATED AT 250 WORDS)
Deletion of exon 15 of the LDL receptor gene is associated with a mild form of familial hypercholesterolemia. FH-Espoo.
Authors: Koivisto P V , Koivisto U M , Kovanen P T , Gylling H , Miettinen T A , Kontula K
Published: June 2011

We describe a mutation of the low-density lipoprotein (LDL) receptor gene, designated familial hypercholesterolemia (FH)-Espoo, which deletes exon 15 of the LDL receptor gene. The mutant receptor is predicted to lack 57 amino acids, including 18 serine and threonine residues, which are the sites of the clustered O-linked sugars of the receptor. Studies on 10 carriers of this gene revealed that FH-Espoo is associated with an exceptionally mild form of FH. Thus, in conditions in which cell proliferation was rendered dependent on the function of LDL receptors, lymphocytes from the patients with the FH-Espoo allele had a growth rate intermediate between those from healthy subjects and patients with the FH-Helsinki gene, a mutation known to abolish LDL receptor function. The in vivo fractional catabolic rate of LDL apolipoprotein B was lower than normal in the two FH-Espoo heterozygotes studied. Although higher than those in healthy controls, the serum LDL cholesterol concentrations in patients with the FH-Espoo gene were significantly lower than those in patients with the FH-Helsinki mutation. The thickness of the Achilles tendons was within the normal limits in subjects with the FH-Espoo gene. Our study suggests that moderate varieties of hypercholesterolemia, ie, those not considered to represent FH, may occasionally be due to subtle LDL receptor gene mutations.
Immunostaining of human autopsy aortas with antibodies to modified apolipoprotein B and apoprotein(a).
Authors: Jürgens G , Chen Q , Esterbauer H , Mair S , Ledinski G , Dinges H P
Published: June 2011

A systematic immunohistochemical study of different stages of atherosclerosis in human aortas was performed using several antibodies. Because oxidation of lipoproteins could be a key event in atherogenesis, an antibody against apolipoprotein B (apoB) from low-density lipoprotein (LDL) modified with the lipid peroxidation-specific aldehyde, 4-hydroxynonenal (4-HNE) (anti-4-HNE-apoB), was raised in rabbits. This antibody recognizing 4-HNE protein adducts was used in concert with an antibody to apo(a) from lipoprotein(a), considered also potentially atherogenic, as well as with an antibody and a monoclonal antibody (mAb) to apoB. Autopsy material from 12 corpses was investigated. The immunohistochemical investigation by the alkaline-phosphatase technique included control specimens regarding postmortem artifacts by autolysis and oxidation. The results from six specimens from five corpses are presented. A positive staining with the antibody to apoB but not with anti-4-HNE-apoB was seen in the normal intima. The thickened intima of early, transitional, and advanced atherosclerotic lesions and atheromata showed a predominantly extracellular staining with all antibodies and the applied mAb. To test the specificity of the staining, antibodies preadsorbed by the appropriate antigens and nonimmune sera were used, giving negative results. These findings indicated a colocalization of epitopes derived from lipid peroxidation of polyunsaturated fatty acids and epitopes specific for apoB and apo(a) during atherogenesis in humans.
Distribution of lipid and raised lesions in aortas of young people of different geographic origins (WHO-ISFC PBDAY Study). World Health Organization-International Society and Federation of Cardiology. Pathobiological Determinants of Atherosclerosis in Youth.
Authors: Tanganelli P , Bianciardi G , Simoes C , Attino V , Tarabochia B , Weber G
Published: June 2011

At the Morphometric Reference Center of the World Health Organization-International Society and Federation of Cardiology PBDAY (Pathobiological Determinants of Atherosclerosis in Youth) project, we studied left hemiaortas of 5- through 34-year-old male and female healthy subjects who died of traumatic injury. The subjects were either of European, American, Asian, or African origin. Three hundred fifty-five thoracic and 343 abdominal left hemiaortas, stained and photographed at the Malmö, Sweden, World Health Organization Reference Center, were studied. Lipid and raised lesion extent was evaluated by using computerized techniques. Probability-of-occurrence maps of lipid and raised lesion distribution were obtained by image processing. Our data have shown that the distributions of atherosclerotic lesions in the aortic intimal surface, which were similar in the different ethnic groups, also prevailed in branching regions, where low-blood flow shear stress and turbulence occur. The areas involved by raised lesions and by lipid lesions only partially overlapped. Lipid lesion extent, which was different among the ethnic groups, continuously increased with age in males but not in females, in whom the increase ceased at an age range from 15 through 24 years. This suggests that ethnic and dietary factors influence the extent but not the distribution of atherosclerotic lesions in the human aorta. Probability-of-occurrence maps also provided evidence that not every fatty streak will develop into a raised lesion, or will not develop quickly.
Identification of novel heparin-releasable proteins, as well as the cytokines midkine and pleiotrophin, in human postheparin plasma.
Authors: Novotny W F , Maffi T , Mehta R L , Milner P G
Published: June 2011

The heparin-releasable proteins are a group of proteins that are targeted to the endothelial surface by attachment to glycosaminoglycans and may have functions specific to the endothelium-blood interface. In this study, heparin-affinity chromatography of human postheparin plasma was used as a method to identify and study novel heparin-releasable proteins. Six proteins seen on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels have increased levels in plasma after intravenous heparin. The six proteins are platelet factor 4, midkine, pleiotrophin, and several novel proteins. Midkine and pleiotrophin are related cytokines that are developmentally regulated, neurotrophic, and mitogenic. Additional studies show that levels of midkine and pleiotrophin peak at 10 to 30 minutes after injection of heparin. Heparin-releasable midkine and pleiotrophin do not originate from blood cells or the kidney. Heparin-releasable midkine may originate from endothelial cells. Soft agar culture of an adenocarcinoma cell line (SW-13) demonstrates growth-stimulating activity similar to that described for pleiotrophin in the heparin-agarose eluate of postheparin plasma but not in the heparin-agarose eluate of preheparin plasma. It is concluded there are more heparin-releasable proteins than previously identified, including midkine and pleiotrophin, and that heparin-affinity chromatography of postheparin plasma is a useful technique for identifying novel heparin-releasable proteins.
Lack of apoA-I is not associated with increased susceptibility to atherosclerosis in mice.
Authors: Li H , Reddick R L , Maeda N
Published: June 2011

The consequences of the lack of apolipoprotein A-I (apoA-I) were evaluated in mice made to lack apoA-I by gene targeting. Inbred strain 129 mice homozygous for the inactive Apoa1 gene and maintained on regular mouse chow had markedly reduced total cholesterol (26% normal) and high-density lipoprotein (HDL) cholesterol (25% normal) levels in their plasma. Their plasma lipoproteins lacked apoA-I and were reduced in all other apolipoproteins but apoE. ApoE comprises about one third of the protein of HDL particles in homozygotes, whereas it is present in only trace amounts in normal HDL. Despite the reduction of HDL cholesterol, no atherosclerotic lesions were observed in any of the homozygous mice evaluated (up to 15 months of age). After being maintained on an atherogenic diet for 4 weeks, total plasma cholesterol of the homozygous mutants increased by 20 mg/dL, while that of normals increased by 60 mg/dL. Mice with mixed 129 and C57BL/6J genetic backgrounds were fed the atherogenic diet for 20 weeks. A small number of foam cells were found attached to the aortic surface in some of the animals, but the extent and occurrence of these depositions were not related to the apoA-I genotype. Our results demonstrate that a lack of apoA-I does not by itself cause atherosclerosis in mice.
Interactions between the monocyte/macrophage and the vascular smooth muscle cell. Stimulation of mitogenesis by a soluble factor and of prostanoid synthesis by cell-cell contact.
Authors: Zhang H , Downs E C , Lindsey J A , Davis W B , Whisler R L , Cornwell D G
Published: June 2011

The effect of soluble factors from the monocyte/macrophage (M phi) on cell proliferation and the functional effects of cell-cell contact on the arachidonic acid (AA) cascade were studied with vascular smooth muscle cells (SMCs). Peripheral blood M phi s were isolated by adherence or in a Percoll gradient, and alveolar M phi s were obtained by lavage. Conditioned medium (CM) was prepared by preincubating M phi s with medium alone or by separating SMC and M phi cocultures by a membrane insert. Cell proliferation (image analysis) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha, radioimmunoassay) were measured in SMCs. Labeled prostanoids and other eicosanoid metabolites were isolated by high-performance liquid chromatography from SMCs prelabeled with 14C-AA. M phi s did not synthesize 6-keto-PGF1 alpha. The CM enhanced proliferation but did not stimulate 6-keto-PGF1 alpha synthesis in SMCs. However, cell-cell contact in cocultures of SMCs with the same concentration of M phi s used to generate CM resulted in increased 6-keto-PGF1 alpha synthesis by SMCs. Since the stimulatory effect of cell contact was not blocked by butylated hydroxytoluene, it could not be attributed to an oxidative burst from M phi s. Functional studies showed that the stimulatory effect of cell contact was enhanced by exogenous free AA and by endogenous AA release through A23187. Release of total radioactivity from prelabeled SMCs was enhanced by cell contact, and this effect was blocked by indomethacin (IM). Cell contact did not increase the release of free AA from prelabeled SMCs, even in the presence of IM. Finally, cell contact only stimulated the formation of prostanoids (IM-sensitive eicosanoid metabolites) from prelabeled SMCs. Lipoxygenase and other products of AA were not formed through cell-cell contact. These data showed that M phi s express a soluble factor that enhances SMC proliferation without affecting prostanoid synthesis. Subsequent cell contact between SMCs and M phi s stimulates prostanoid synthesis, which may possibly serve as a local and focal homeostatic mechanism for the regulation of uncontrolled SMC proliferation in atherogenesis.