bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary factors relate to cardiovascular risk factors in early life. Bogalusa Heart Study.
Authors: Nicklas T A , Farris R P , Smoak C G , Frank G C , Srinivasan S R , Webber L S , Berenson G S
Published: June 2011

Relationships between diet and cardiovascular disease risk factors were studied in a cohort of infants in Bogalusa, Louisiana. The 24-hour dietary recalls and cardiovascular measurements were obtained on each child at age 6 months, yearly through age 4, and again at age 7 (cardiovascular measurements only). At ages 4 and 7, children with persistently high intakes of dietary cholesterol (three or more measurements in the upper tertile) had levels of serum total cholesterol approximately 14 mg/dl higher than children whose intakes of cholesterol were not persistently high. Children in the upper tertile for dietary cholesterol had levels of low density lipoprotein cholesterol (15 mg/dl at age 4 and 18 mg/dl at age 7) higher than children in the lower tertile for dietary cholesterol. Children with high intakes of animal fat were 2 to 6 kg heavier (p less than 0.05) than those with lower intakes. Changes in dietary cholesterol correlated significantly with changes in serum total cholesterol (r = 0.42) and low density lipoprotein cholesterol (r = 0.50) from 6 months to 4 years of age. Changes in subscapular skinfold measurements correlated significantly with changes in intake of total protein (r = 0.31), total fat (r = 0.25), starch (r = 0.31), and energy (r = 0.39) from ages 6 months to 4 years. Results indicate that tracking of dietary components and their relationships with cardiovascular disease risk factors can be detected at an early age. These findings may well be the groundwork for later studies of obesity and the early onset of hyperlipoproteinemia.
High density lipoprotein cholesterol, total cholesterol screening, and myocardial infarction. The Framingham Study.
Authors: Abbott R D , Wilson P W , Kannel W B , Castelli W P
Published: June 2011

The relation between high density lipoprotein cholesterol (HDL-C) and the development of myocardial infarction was examined in 2425 subjects, aged 50 to 79 years, who were enrolled in the Framingham Study from 1969 to 1971. After 12 years of follow-up, men in the bottom three quartiles of HDL-C (less than or equal to 52 mg/dl) experienced a 60% to 70% excess of myocardial infarction as compared to men whose HDL-C levels were higher (p less than 0.05). The effect of HDL-C was especially strong in women. In separate comparisons to the 4th quartile of HDL-C (greater than or equal to 67 mg/dl), the risk of myocardial infarction increased from a fourfold excess in the adjacent 3rd quartile (56 to 66 mg/dl, p less than 0.01) to a nearly sixfold excess in the 1st quartile (less than or equal to 46 mg/dl, p less than 0.001). These results persisted after adjusting for age and other risk factors. In addition, a significant effect of HDL-C remained in subjects who had the lowest concentrations of total cholesterol (less than or equal to 192 mg/dl in men and 211 mg/dl in women) in which 29% had levels of HDL-C (less than or equal to 36 mg/dl in men and 46 mg/dl in women) that were associated with a marked elevation in the incidence of myocardial infarction. We conclude that screening for total cholesterol alone in men and women aged 50 and older may not adequately identify the coronary candidate.(ABSTRACT TRUNCATED AT 250 WORDS)
Lp(a) phenotyping by immunoblotting with polyclonal and monoclonal antibodies.
Authors: Kraft H G , Dieplinger H , Hoye E , Utermann G
Published: June 2011

A new method that allows rapid phenotyping of genetic Lp(a) glycoprotein types in large numbers of samples is described. The method is based on sodium dodecyl sulfate gel electrophoresis of reduced serum or plasma in horizontal slab gels followed by immunoblotting with polyclonal anti-Lp(a) lipoprotein or monoclonal anti-Lp(a) glycoprotein antibodies. Phenotyping of 194 unrelated, healthy subjects resulted in Lp(a) allele frequencies of Lp(a)B = 0.013, Lp(a)S1 = 0.032, Lp(a)S2 = 0.106, Lp(a)S3 = 0.096, Lp(a)S4 = 0.156, and Lp(a)O = 0.600, and confirmed the recently recognized association of Lp(a) glycoprotein phenotype with Lp(a) lipoprotein concentration. The new procedure is suitable for large-scale population, genetic, and epidemiologic studies and may be important for atherosclerotic risk assessment.
Effect of moderate exercise on serum lipids in young men with low high density lipoprotein cholesterol.
Authors: Raz I , Rosenblit H , Kark J D
Published: June 2011

Fifty-five healthy, sedentary, nonsmoking, and nonobese 24- to 26-year-old men who had low plasma concentrations of high density lipoprotein (HDL) cholesterol were selected for a study of the effect of short-term exercise on plasma lipid and lipoprotein concentrations. The participants were randomized into two groups. Of these, 28 were assigned to a 9-week program of submaximal aerobic exercise three times weekly, and 27 were assigned to a nonexercising control group. Changes in physical fitness were assessed by increments in estimated maximal oxygen consumption; this increased by 15% in the exercise group (p less than 0.001) but remained unchanged in the control group. During the study, body weights and skinfold thicknesses of both groups remained essentially unchanged after 9 weeks. There was no significant difference between the trial groups in total cholesterol, HDL cholesterol, calculated low density lipoprotein cholesterol, or in the HDL2 and HDL3 subfractions. Triglyceride levels were lower by 19 mg/dl in the exercise group as compared to the control group (p less than 0.05). We conclude that moderate aerobic exercise of 9 weeks duration in the absence of weight loss in young males with initially low HDL cholesterol did not influence their HDL cholesterol levels.
In vivo transfer of cholesteryl ester from high and low density plasma lipoproteins into human aortic tissue.
Authors: Stender S , Hjelms E
Published: June 2011

For the study of cholesteryl ester transfer from different plasma lipoproteins into human aortic tissue, patients scheduled for reconstructive aortic surgery were intravenously injected with autologous in vitro labeled lipoproteins 20 to 24 hours before aortic intima-media samples were obtained during the operation. The injectate contained high density lipoproteins (d greater than 1.063) labeled with 3H-cholesteryl ester and lipoproteins of lower density (d less than 1.063) labeled with 14C-cholesteryl ester or lipoproteins with the opposite labeling. In 16 aortic tissue samples (some with visible atherosclerosis) from 11 normocholesterolemic patients, the aortic influx of total cholesteryl ester was 1 to 50 nmol x cm-2 x day-1. Some 39% +/- 3% (mean +/- SEM) of the influx was derived from high density lipoproteins, which in plasma accounted for only 22% +/- 2% (mean +/- SEM) of the esterified cholesterol. The findings suggest that: 1) esterified cholesterol from the two lipoprotein fractions in plasma enter the aortic intima by the same mechanism, and 2) influx of cholesteryl ester from the smaller, high density lipoproteins is greater than influx from the larger, lower density lipoproteins considering their concentrations in plasma. In some patients, the cholesterol content in the intima-media tissue with no visible atherosclerosis corresponded to only a few months of continuous cholesteryl ester influx. This time is short considering the age of the patients and, therefore, indicates that removal of esterified cholesterol from the intima-media is of major importance in preventing cholesterol deposition in the arterial wall.
Evidence for surface entrapment of cholesterol-rich lipoproteins in luteinized ovary.
Authors: Reaven E , Boyles J , Spicher M , Azhar S
Published: June 2011

Previous studies showed that perfused 125I-labeled low and high density lipoproteins (LDL, HDL) have affinity for specialized microvillar regions of luteal cells in hormone-primed, luteinized rat ovaries. In the current report, we re-examined the interaction of cholesterol-rich lipoproteins with these specialized plasma membrane regions using native lipoproteins visualized as discrete particles by standard electron microscopic techniques. In ovaries perfused with the various lipoproteins, spherical particles (varying in size from 12 to 28 nm depending on the particle used) were found over the surfaces of all luteal cells and filling up extensive "channel" space formed by the apposed plasma membranes of adjacent microvilli or cytoplasmic surfaces. Only 30% of these tissue-associated particles were removable after prolonged washing with perfused media or heparin. Few intact particles were found inside the cells, despite the fact that the lipoproteins induced a substantial hormone response by the ovary. To determine the total protein internalized by cells during the course of the experiments, parallel biochemical experiments were carried out with nonreleasable (14C-sucrose-coupled) human LDL. Of the total bound 14C-sucrose LDL, only 8.5% was degraded (trichloroacetic acid-soluble) and presumed internalized by the cells. Thus, while large numbers of cholesterol-rich lipoprotein particles interact with the luteal cell surface in specialized microvillar channels and elicit a progesterone response, relatively few intact lipoprotein particles appear to enter the cells to be degraded. We speculate that in the luteinized ovary, a large majority of the lipoprotein-cholesterol transfer occurs at the surface of the luteal cells, and that the membranes of the microvillar channels are involved in this process.
Endothelium from diverse vascular sources synthesizes platelet-activating factor.
Authors: Whatley R E , Zimmerman G A , McIntyre T M , Prescott S M
Published: June 2011

Stimulation of cultured bovine endothelial cells from aorta, pulmonary artery, coronary artery, and vena cava with calcium ionophore A23187, adenosine triphosphate (ATP), bradykinin, and angiotensin II resulted in production of platelet-activating factor (PAF), 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. In pulmonary artery endothelial cells, maximal accumulation occurred within 20 minutes, and the PAF remained cell-associated. This response was concentration-dependent with a maximal effect at 10(-8)M bradykinin and 10(-6)M angiotensin II. Stimulation of in situ endothelial cells on isolated strips of bovine pulmonary artery with calcium ionophore, ATP, and bradykinin also resulted in production of PAF. In cultured pulmonary artery endothelial cells, PAF appeared only in response to the same agonists that caused prostacyclin (PGI2) release. These findings are similar to earlier studies with human umbilical vein endothelial cells and suggest that the production of PAF and the arachidonate metabolite PGI2 are tightly linked in these vessels. Aortic endothelial cells, both in culture and on isolated strips of aorta, also produced PAF in response to bradykinin in a time-and concentration-dependent fashion. Cultured endothelial cells from coronary vessels and the inferior vena cava accumulated PAF when appropriately stimulated as well. The finding that both cultured endothelial cells and in situ, ex vivo endothelium from diverse vascular sites produce PAF when appropriately stimulated suggests that this is a generalized response of endothelial cells. Because PAF has potent vasoactive, pro-aggregatory, and pro-inflammatory effects, the results from these experiments suggest that the local accumulation of this lipid may be important in vascular injury and inflammation.
Suppression of foam cell lesions in hypercholesterolemic rabbits by inhibition of thromboxane A2 synthesis.
Authors: Skrinska V A , Konieczkowski M , Gerrity R G , Galang C F , Rebec M V
Published: June 2011

Hypercholesterolemia induces adhesion of blood-borne monocytes to vascular endothelium and their subsequent migration into the intima, where foam cell lesions subsequently develop. The regulating mechanisms for the adhesion and migration are unclear. In this study, a specific thromboxane A2 (TXA2) synthetase inhibitor, UK-38485, was used to treat rabbits fed an atherogenic diet to determine whether inhibition of TXA2, the major metabolite of arachidonic acid in monocytes, affects lesion development. Rabbits were fed a diet supplemented with 2% cholesterol and 8% peanut oil for 12 weeks with or without UK-38485 at a dosage that maintained 80% to 90% inhibition of TXA2 formation in serum. The treatment with UK-38485 had no effect on total serum cholesterol. Both the treated and untreated groups developed subpopulations of high and low responders with respect to the extent of lesion coverage, forming a bimodal distribution. The treatment with UK-38485 significantly (p less than 0.001) reduced the percentage of the thoracic aorta covered by lesions when treated low responders (5.3 +/- 1.0%, n = 12) were compared to untreated low responders (23.6 +/- 2.9%, n = 12). However, UK-38485 had no effect when treated high responders (76.3%, n = 3) were compared to untreated high responders (72.0%, n = 12). Lesion coverage was not correlated with serum cholesterol levels. Stimulation of isolated rabbit monocytes in autologous plasma with 0.66 mM arachidonic acid in the presence of increasing concentrations of UK-38485 caused a dose-dependent inhibition of TXA2 and a concurrent increase in prostaglandin E2 (PGE2).(ABSTRACT TRUNCATED AT 250 WORDS)
Coronary arteriosclerosis in Atlantic salmon. No regression of lesions after spawning.
Authors: Saunders R L , Farrell A P
Published: June 2011

The incidence and severity of coronary arteriosclerosis were studied in 209 wild and cultured Atlantic salmon (Salmo salar L.) during various stages of recovery of bodily condition after spawning. All recently spawned fish had lesions of moderate to extreme severity. The incidence of lesions for each fish was high (73% to 94% of all arterial cross-sections examined). The incidence and severity of lesions did not decrease during 5 months in a group of wild salmon reconditioned in the laboratory. Wild salmon that were examined in the spring angling fishery in the Miramichi River, New Brunswick, about 5 months after spawning had a high incidence (89%) of severe lesions, not significantly different from recently spawned salmon from the same and another river. A population of cultured salmon sampled at intervals from a sea cage during 9 months after spawning showed no evidence of lesion regression, but rather a continued increase in both incidence and severity during recovery of bodily condition and growth. Thus, in contrast with previous studies with steelhead trout and Atlantic salmon where the possibility of lesion regression has been suggested, our observations on a large number of Atlantic salmon from various sources gave no evidence of lesion regression. Coronary arteriosclerosis in Salmo salar appears to be a progressive condition, which continues during recovery of bodily condition and growth after spawning.
Imaging human atherosclerosis with 99mTc-labeled low density lipoproteins.
Authors: Lees A M , Lees R S , Schoen F J , Isaacsohn J L , Fischman A J , McKusick K A , Strauss H W
Published: June 2011

The feasibility of localizing human atherosclerotic plaques by gamma scintillation camera external imaging with technetium-99m-labeled low density lipoproteins (99mTc-LDL) was tested in 17 patients who had atherosclerosis. Imaging demonstrated focal accumulation of radiolabel consistent with 99mTc-LDL sequestration by plaques in the carotid, iliac, or femoral vessels of four patients 8 to 21 hours after intravenous injection of the radiopharmaceutical. Focal accumulation of 99mTc-LDL also appeared in the location of coronary lesions in four patients, but this accumulation could not be distinguished with certainty from residual blood pool radioactivity. When carotid endarterectomy specimens from six patients who received 99mTc-LDL 1 day before endarterectomy were examined, the specimens had focal accumulations of radiolabel, with two to four times greater radioactivity in some regions of each specimen than in others; this occurred whether or not the lesions were detected on the gamma camera images. Lesion composition may have determined whether accumulation was quantitatively sufficient to produce an external image. Histologically, the imaged carotid specimen had abundant foam cells and macrophages and poorly organized intramural blood consistent with a plaque hemorrhage; in contrast, nonimaged endarterectomy specimens were mature, fibrocalcific plaques. We conclude that: 1) 99mTc-LDL did accumulate in human atherosclerotic plaques; 2) in some patients, the accumulation of 99mTc-LDL was sufficient for detection by gamma camera imaging; 3) the amount of LDL that accumulated appeared to depend on lesion composition; and 4) the design of new radiopharmaceuticals with reduced residual blood pool activity relative to plaque accumulation should lead to improved external imaging of atherosclerosis.
Serum lipids and apolipoprotein levels in women with acute myocardial infarction.
Authors: Johansson S , Bondjers G , Fager G , Wedel H , Tsipogianni A , Olofsson S O , Vedin A , Wiklund O , Wilhelmsson C
Published: June 2011

In this study covering more than 150,000 person-years from women younger than 55 years of age, 61 survived a first acute myocardial infarction (AMI). Of these, 59 were compared with a random sample from the same population regarding serum lipids and apolipoproteins (apo) A-I, A-II, B, and E, as well as several other cardiovascular risk factors. Mean values of serum cholesterol, triglycerides, apo B, and apo E were significantly higher and high density lipoprotein cholesterol and apo A-I were significantly lower among patients with infarction than among controls. Those who sustained and survived an AMI more often had a history of hypertension and of tobacco smoking than did the controls. Cigarette smoking, a history of hypertension, age, high serum triglycerides and apo E, as well as low levels of apo A-I, were independently and significantly associated with infarction. Sixty percent of the cases and 11% of the controls were distributed in the highest quartile of risk. A major contribution to the association with AMI was accounted for by the conventional risk factors, cigarette smoking and hypertension, as well as high serum triglycerides. In this group of relatively young women, high serum triglycerides were strongly associated with infarction, while levels of serum cholesterol were not.
Isolation of low density lipoprotein from atherosclerotic vascular tissue of Watanabe heritable hyperlipidemic rabbits.
Authors: Daugherty A , Zweifel B S , Sobel B E , Schonfeld G
Published: June 2011

Atherogenic properties of low density lipoproteins (LDL) in vivo may reflect modification of lipoproteins associated with endothelial translocation and exposure to extracellular matrix and interstitial fluid. To examine whether modifications of LDL occur in vivo, lipoproteins were isolated from plasma and vascular tissue of Watanabe heritable hyperlipidemic (WHHL) rabbits. LDL was extracted from vascular tissue (LDL-V) by homogenization in the presence of a sodium carbonate buffer. Control experiments demonstrated that modifications did not occur under the preparative conditions used to release LDL from tissue. LDL-V contained less esterified cholesterol, but more cholesterol esters, than did LDL from plasma (LDL-P). The diameters of both LDL-V and LDL-P followed gaussian distributions, but LDL-V particles were smaller (20.3 +/- 0.1 and 26.3 +/- 0.1 nm). Mild lipid peroxidation was evident in LDL-V. The sphingomyelin content was increased in LDL-V, with less phosphatidylcholine than in LDL-P. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) indicated that apolipoprotein B was depleted in LDL-V, but Western blot analyses identified lower molecular weight proteins antigenically related to apolipoprotein B. LDL-V markedly stimulated cholesterol esterification in mouse peritoneal macrophages and also in rabbit alveolar macrophages, a cell type that did not respond to acetylated LDL. LDL-V was not recognized by cultured rabbit skin fibroblasts. Thus, LDL isolated from atherosclerotic vascular tissue in vivo was modified in a fashion that could confer atherogenic properties reflected by augmentation of cholesterol esterification in macrophages in vitro.
Independent effects of diet and nutritional status on apoprotein B gene expression in rabbit.
Authors: Fisher E A , Anbari A , Klurfeld D M , Kritchevsky D
Published: June 2011

The separate effects of dietary composition and time of nutrient intake on apoprotein B (apo B) gene expression in rabbit intestine and liver were determined. After an overnight fast, there were insignificant effects of the long-term consumption of a diet containing saturated fat on the tissue levels of apo B mRNA, although plasma cholesterol levels were elevated as compared to those of animals consuming a diet containing unsaturated fat. However, when the animals were studied 2 hours after receiving a gastric tube feeding of a portion of their test diets after an overnight fast, there was a twofold increase in the intestinal apo B mRNA level and a similar increase in the transcriptional activity of the apo B gene independent of dietary composition. We conclude that, with the diets we used, nutrient intake alone has, in rabbits, a major effect on apo B gene expression at the level of transcription. This factor should be taken into account when designing studies of intestinal gene expression.
Interaction of lipoprotein Lp(a) and low density lipoprotein with glycosaminoglycans from human aorta.
Authors: Bihari-Varga M , Gruber E , Rotheneder M , Zechner R , Kostner G M
Published: June 2011

The lipoprotein complexing activity of glycosaminoglycans (GAG) prepared from human aortas with lipoprotein Lp(a) in comparison to low density lipoproteins (LDL) was determined tubidimetrically in the presence of Ca++. In control experiments, purified chondroitin-6 sulfate and proteoglycans (PG) were used. Lp(a) exhibited approximately a threefold higher reactivity. Analyzing the chemical composition of the complexes, we found that Lp(a) had greater than fourfold higher binding capacity for GAG. The binding capacity of Lp(a) to PG was 3.4-fold higher as compared to LDL. The binding capacity of both lipoproteins for chondroitin-6 sulfate was only 50% in comparison to GAG, but again Lp(a) was four times more reactive. Neuraminidase treatment of LDL or Lp(a) did not interfere with GAG or chondroitin-6 sulfate binding. If, on the other hand, Lp(a) was treated with dithiothreitol and the Lp(a)-specific protein (apoprotein [apo] a) was removed, the GAG binding was reduced by about 45%. Apo a by itself gave no insoluble complexes with GAG. LDL and Lp(a)-s GAG and -LP(a)-PG complexes were incubated with mouse peritoneal macrophages (MPM), and the stimulation of cholesteryl ester formation was studied. At identical lipoprotein cholesterol concentrations, Lp(a)-GAG complexes exhibited a 1.3-fold higher stimulation of cholesterol esterification as compared to LDL-GAG. This difference was even more striking if lipoproteins were compared at a molar basis. PG-lipoprotein complexes were much more active with respect to interactions with MPM. The highest amount of cholesterol ester formation upon incubation with MPM was found with PG-Lp(a) complexes.(ABSTRACT TRUNCATED AT 250 WORDS)
Test of effect of lipid lowering by diet on cardiovascular risk. The Minnesota Coronary Survey.
Authors: Frantz I D , Dawson E A , Ashman P L , Gatewood L C , Bartsch G E , Kuba K , Brewer E R
Published: June 2011

The Minnesota Coronary Survey was a 4.5-year, open enrollment, single end-time double-blind, randomized clinical trial that was conducted in six Minnesota state mental hospitals and one nursing home. It involved 4393 institutionalized men and 4664 institutionalized women. The trial compared the effects of a 39% fat control diet (18% saturated fat, 5% polyunsaturated fat, 16% monounsaturated fat, 446 mg dietary cholesterol per day) with a 38% fat treatment diet (9% saturated fat, 15% polyunsaturated fat, 14% monounsaturated fat, 166 mg dietary cholesterol per day) on serum cholesterol levels and the incidence of myocardial infarctions, sudden deaths, and all-cause mortality. The mean duration of time on the diets was 384 days, with 1568 subjects consuming the diet for over 2 years. The mean serum cholesterol level in the pre-admission period was 207 mg/dl, falling to 175 mg/dl in the treatment group and 203 mg/dl in the control group. For the entire study population, no differences between the treatment and control groups were observed for cardiovascular events, cardiovascular deaths, or total mortality. A favorable trend for all these end-points occurred in some younger age groups.
Apolipoprotein E2(Arg158----Cys) frequency in a hyperlipidemic French-Canadian population of apolipoprotein E2/2 subjects. Determination by synthetic oligonucleotide probes.
Authors: Weisgraber K H , Newhouse Y M , Taylor J M , Tuan B , Nestruck A C , Davignon J , Mahley R W
Published: June 2011

An underlying cause of type III hyperlipoproteinemia is the presence of variant forms of apolipoprotein (apo) E that are defective in binding to apo B,E low density lipoprotein receptors. This disorder is associated almost exclusively with the apo E2/2 phenotype. However, structural and functional heterogeneity have been demonstrated within this phenotype. The apo E2(Arg158----Cys) variant, displaying 1% of normal apo E3 binding activity, is the most defective known form. In this study, we describe a method in which a pair of 19-mer synthetic oligonucleotide probes were used to distinguish between DNA coding for arginine or cysteine at position 158 in apo E. The specificity of the probes was demonstrated by using DNA from subjects whose apo E protein sequence or phenotype was known. The probes were used to screen a French-Canadian population of 34 apo E2/2 subjects to determine the frequency of the apo E2(Arg158----Cys) variant. All 34 subjects, most of whom displayed clinical or biochemical features of type III hyperlipoproteinemia, were found to be homozygous for apo E2(Arg158----Cys), strongly suggesting that this variant is the most common form of apo E2 within this ethnic and clinical population. In addition, the utility of this approach in detecting new apo E mutants was demonstrated when DNA from one of the apo E3/3 control subjects, whose family has a history of hyperlipidemia and coronary artery disease, reacted with both probes. This result suggests that this subject is heterozygous for normal apo E3 and a new apo E3 variant that is likely to be functionally equivalent to apo E2(Arg158----Cys).
Regulation of major histocompatibility gene expression in human vascular smooth muscle cells.
Authors: Warner S J , Friedman G B , Libby P
Published: June 2011

Human atheromata, but not normal blood vessels, contain numerous smooth muscle cells (SMC) that bear class II major histocompatibility (MHC) antigens. These lesions also contain leukocytes that can secrete cytokines, which may modulate SMC functions. Because of morphologic evidence for immune-activated (class II+) SMC in vascular lesions, we studied the regulation by cytokines of MHC gene expression in SMC cultured from human vessels. Under basal conditions, these SMC contained mRNA for class I MHC (detected by Northern blotting with a cDNA probe for HLA-B7) and expressed surface class I MHC product determined by enzyme-linked immunoassay with monoclonal antibody (MAb) W6/32. Unstimulated SMC contained little or no class II MHC mRNA (probed with HLA-DR alpha cDNA) or surface antigen (examined using MAb I2). Secretory products of activated human leukocytes (the cell-free supernatant of a mixed leukocyte reaction) induced class II MHC antigen expression by SMC after 3 days. Treatment of SMC with interferon (IFN)-alpha or -beta (1000 U/ml for 72 hours) increased class I MHC mRNA content and surface antigen but did not alter class II expression. Immune IFN (IFN-gamma), a leukocyte product known to induce class II MHC expression in classical antigen presenting cells as well as epithelial and endothelial cells, not only increased class I MHC expression by SMC but also induced substantial levels of class II MHC mRNA and surface antigen. IFN-gamma (ED50 approximately 10 U/ml) increased class II MHC mRNA maximally after 2 to 3 days and surface expression linearly from 1 to 4 days. Immunohistochemical study demonstrated few class II+ SMC in cultured human SMC under basal conditions but homogeneous expression of high levels of DR antigen after exposure to IFN-gamma for 3 days. Neither interleukin-1 (IL-1 alpha or beta), tumor necrosis factor alpha (TNF), nor endotoxin altered class II expression by SMC. Local secretion of IFN-gamma by activated leukocytes may account for the presence of HLA-DR+ SMC in the human atheroma. Immune activation of SMC might participate in the pathogenesis of vasculitis and arteriosclerosis, particularly in the form found in the coronary arteries of transplanted hearts.
Plasma plasminogen activator inhibitor-1 in angina pectoris. Influence of plasma insulin and acute-phase response.
Authors: Juhan-Vague I , Alessi M C , Joly P , Thirion X , Vague P , Declerck P J , Serradimigni A , Collen D
Published: June 2011

Plasminogen activator inhibitor-1 (PAI-1) is an important physiological inhibitor of fibrinolysis. It circulates in blood both in free active form and in inactive form complexed with tissue type plasminogen activator (t-PA). Control mechanisms for its synthesis and release from hepatocytes and endothelial cells are important in the pathogenesis of thrombosis. Possible risk factors for myocardial infarction include high insulin and PAI-1 levels, which correlate with one another in healthy subjects, and fibrinogen, which together with PAI-1, is an acute-phase reactant. We therefore studied the interrelationships between PAI-1, plasma insulin, and acute-phase proteins in 67 patients with angina pectoris. Plasma insulin correlated strongly (r = 0.59, p less than 0.001) with PAI activity, free PAI-1 antigen (r = 0.60, p less than 0.001), and total PAI-1 antigen (r = 0.58, p less than 0.001). The acute-phase proteins, fibrinogen and C-reactive protein, correlated significantly with t-PA antigen, total PAI-1 antigen, and PAI-1/t-PA complexes but not with PAI activity or free PAI-1. The results suggest that insulin stimulates synthesis and release of free PAI-1 (probably via hepatocytes as previously shown with cell culture) and that endothelial cell synthesis and release of t-PA, together with PAI-1, reflects a nonspecific acute-phase response to chronic vascular disease. Hyperinsulinemia found in patients with angina pectoris could play a role in the development of myocardial infarction via the induction of high plasma PAI-1 activity.
Atherosclerosis in rabbit vein grafts.
Authors: Zwolak R M , Kirkman T R , Clowes A W
Published: June 2011

Human coronary saphenous vein bypass grafts develop atherosclerosis more readily than do grafts made of internal mammary artery. The reasons for this increased susceptibility, particularly in the presence of hyperlipidemia, are not known. In this study in rabbits, we investigated the possibility that the increased susceptibility might be attributed to increased smooth muscle proliferation and foam cell accumulation in vein grafts compared to native artery. Hypercholesterolemic and control rabbits underwent placement of jugular vein grafts in the carotid artery. Dietary cholesterol content was adjusted to maintain serum cholesterol levels of 200 to 600 mg/dl in the fat-fed rabbits. The vein graft intimal thickness in hypercholesterolemic rabbits was greater than in normolipemic rabbits at 3 and 6 months after implant. The increased thickness in the hypercholesterolemic group was largely accounted for by an accumulation of lipid-laden macrophages. Medial thicknesses increased during the first month, remained constant at later times, and were similar in control and hypercholesterolemic animals. In both groups, endothelial and smooth muscle cell proliferation (thymidine labeling) increased immediately after graft implantation and declined at 3 and 6 months. No incremental mitogenic stimulus could be attributed to the hypercholesterolemia. In immunohistochemical preparations, the large foam cells were noted to be macrophages, and the intimal proliferating cells, to be smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of cholesterol feeding on lipolytic activities in high- and low-responding rhesus monkeys.
Authors: Bhattacharyya A K , Baker H N , Eggen D A , Malcom G T , Roheim P S , Strong J P
Published: June 2011

We compared the activities of lipoprotein (LPL) and hepatic lipase (HL) in postheparin plasma in groups of high- and low-responding rhesus monkeys fed a low cholesterol diet followed by a high cholesterol diet. Cholesterol feeding resulted in a two-phase response in lipolytic activities: an initial phase lasting about 21 days that was similar in the two groups, followed by the second phase in which major differences became apparent between the groups. In the initial phase, LPL and HL activities increased along with plasma cholesterol and high density lipoprotein (HDL) cholesterol, but there was no change in plasma triglycerides or apolipoprotein (apo) A-I levels. These changes suggest that both high and low responders respond in a similar manner to metabolize an increased lipid load and that both groups continue to remove triglyceride efficiently while cholesterol accumulation begins. The second phase (between 21 and 42 days and thereafter) in high responders was characterized by a decrease in LPL and HL activities along with plasma HDL cholesterol and apo A-I levels, continued increase in plasma cholesterol, and a slow increase in plasma triglycerides. In low responders, LPL activity was maintained at a high level, HL activity decreased to the basal level, and plasma lipids were unchanged. All changes occurred simultaneously, suggesting metabolic relationships between plasma lipolytic activities, plasma lipids, and apolipoprotein.
Oxidative modification of beta-very low density lipoprotein. Potential role in monocyte recruitment and foam cell formation.
Authors: Parthasarathy S , Quinn M T , Schwenke D C , Carew T E , Steinberg D
Published: June 2011

Oxidative modification of low density lipoprotein (LDL) generates a form that is degraded much more rapidly by macrophages and may thus be more atherogenic than unoxidized LDL. Recently, we provided evidence that oxidative modification of LDL may play a significant role in the generation of fatty streaks in the LDL receptor-deficient rabbit. The major lipoprotein in cholesterol-fed animals is the beta-very low density lipoprotein (beta-VLDL). Since beta-VLDL is avidly taken up by macrophages, it could lead to foam cell formation without the need for oxidative modification or modification of other kinds. However, the present studies show that beta-VLDL can be oxidized by incubation with endothelial cells or with copper ions. Oxidized beta-VLDL was degraded by macrophages at about twice the rate of unoxidized beta-VLDL, and it stimulated cholesterol esterification twice as much as unoxidized beta-VLDL. The degradation of oxidized beta-VLDL was inhibited either by oxidized beta-VLDL itself or by oxidized LDL, but not by unoxidized beta-VLDL. beta-VLDL was chemotactic for human monocytes and contained significant amounts of lysophosphatidylcholine, previously shown to be a chemotactic agent. In summary, oxidized LDL is degraded by macrophages proportionately more than oxidized beta-VLDL as compared to the unmodified lipoproteins. However, the twofold increase may, nevertheless, be significant in the atherogenicity of beta-VLDL.
Apolipoprotein A-I metabolism in cynomolgus monkey. Identification and characterization of beta-migrating pools.
Authors: Melchior G W , Castle C K
Published: June 2011

Fresh plasma from control (C) and hypercholesterolemic (HC) cynomolgus monkeys was analyzed by agarose electrophoresis-immunoblotting with antibody to cynomolgus monkey apolipoprotein (apo) A-I. Two bands were evident on the autoradiogram: an alpha-migrating band (high density lipoprotein) and a beta-migrating band that comigrated exactly with cynomolgus monkey low density lipoprotein (LDL). The presence of beta-migrating apo A-I in the plasma of these monkeys was confirmed by Geon-Pevikon preparative electrophoresis, crossed immunoelectrophoresis, and isotope dilution studies in which radiolabeled apo A-I was found to equilibrate also with alpha- and beta-migrating pools of apo A-I in the plasma. Subfractionation of C and HC plasma by agarose column chromatography (Bio-Gel A-0.5M and A-15M) followed by agarose electrophoresis-immunoblotting indicated that the beta-migrating apo A-I in C was relatively homogeneous and eluted with proteins of Mr approximately 50 kD [apo A-I(50 kD)], whereas two beta-migrating fractions were identified in HC, one that eluted with the 50-kD proteins, and the other that eluted in the LDL Mr range [apo A-I(LDL)]. The apo A-I(LDL) was precipitated by antibody to cynomolgus monkey apo B. The apo A-I(50 kD) accounted for 5 +/- 1% (mean +/- SD) of the plasma apo A-I in C plasma, and 15 +/- 7% in HC plasma. No apo A-I(LDL) was detected in C plasma, but that fraction accounted for 9 +/- 7% of the apo A-I in HC plasma. These data establish the presence of multiple pools of apo A-I in the cynomolgus monkey, which must be taken into consideration in any comprehensive model of apo A-I metabolism in this species.
A biologically plausible model of thickening of arterial intima under shear.
Authors: Friedman M H
Published: June 2011

A biologically plausible model of the early thickening of the arterial intima has been developed to interpret experimental data relating hemodynamic shear to human intimal morphology. The model included many processes known or commonly believed to take place in the vascular intima, including: smooth muscle cell migration, proliferation, metabolism, and expression of extracellular matrix; lipoprotein kinetics and binding; and monocyte chemotaxis, conversion to macrophage, and foam cell formation. Certain of these processes were allowed to be shear-dependent. The best fit to the data was obtained when smooth muscle cell accumulation was more rapid, and extracellular matrix expression proceeded more slowly where the fluid shear was relatively high and unidirectional. This result is consistent with the earlier inference that competing shear-dependent processes take place in the wall; it is also consistent with the notion that intimal thickening might be part of an adaptive mechanism by which the artery maintains a favorable shear environment.
Effect of dietary omega-3 fatty acid on serum lipids, platelet function, and atherosclerosis in Watanabe heritable hyperlipidemic rabbits.
Authors: Clubb F J , Schmitz J M , Butler M M , Buja L M , Willerson J T , Campbell W B
Published: June 2011

Omega-3 fatty acids have been shown to lower plasma cholesterol and triglyceride concentrations in humans. However, the effects of these fatty acids on the interactions among lipid concentrations, platelet activity, and atherogenesis have not been characterized in humans or in animals with low density lipoprotein (LDL) receptor deficiencies. To test the hypothesis that omega-3 fatty acids exert a protective effect in LDL receptor-deficient animals by lowering hyperlipidemia, reducing platelet aggregation, and reducing the severity of atherosclerosis, we evaluated young homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits that were fed omega-3 fatty acids. One-month-old male and female WHHL rabbits were placed on either a control diet (standard laboratory rabbit chow) or a diet supplemented with Menhaden fish oil (MFO), which contained eicosapentaenoic acid (EPA). Consumption measurements during the 5 months of the study indicated that the MFO-fed group received 150 to 200 mg/kg/day of EPA. Six-month-old, MFO-fed, female WHHL rabbits had significantly lower plasma concentrations of total cholesterol (582 +/- 20 mg/dl vs. 856 +/- 44 mg/dl, control, p less than 0.05) and triglycerides (266 +/- 21 mg/dl vs. 459 +/- 15 mg/dl, control, p less than 0.05), with lower serum/plasma lipoprotein concentrations [very low density lipoprotein (VLDL), LDL, high density lipoprotein (HDL)] compared to control female WHHL rabbits. Male MFO-fed rabbits had only significantly lower VLDLs (46 +/- 9 mg/dl) compared to control male WHHL rabbits (156 +/- 9 mg/dl, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of exercise-induced weight loss on low density lipoprotein subfractions in healthy men.
Authors: Williams P T , Krauss R M , Vranizan K M , Albers J J , Terry R B , Wood P D
Published: June 2011

One-year changes in low density lipoprotein (LDL) peak flotation (Sf) rate and serum mass concentrations of LDL of Sf 0 to 7 (small LDL), LDL of Sf 7 to 12 (large LDL), intermediate density lipoprotein (IDL) of Sf 12 to 20, and very low density lipoprotein (VLDL) of Sf 20 to 400 were compared between men assigned at random to a 1-year exercise program (N = 48) or to a sedentary control condition (N = 31). Distance run among exercisers varied substantially (mean +/- SD: 12.7 +/- 8.9 km/week). Mean changes were not significantly different between the exercise and control groups for any of the low to very low density lipoprotein measurements. However, within the exercise group: 1) distance run correlated negatively with changes in the mass concentrations of small LDL; and 2) weight loss and reduced upper body obesity correlated positively with changes in small LDL, IDL, and VLDL mass and negatively with change in LDL peak flotation rate. Analyses with partial correlations suggest that weight loss may primarily affect LDL mass distributions through metabolic processes associated with high density lipoprotein2 or small VLDL (Sf 20 to 60). The decrease in small LDL concentrations and the increase in LDL peak flotation rate suggest that exercise-induced weight loss may be effective in reducing coronary heart disease risk in persons genetically predisposed to a high-risk lipoprotein profile.
Metabolism of acetylated low density lipoproteins by monocyte-derived macrophages from patients with Werner's syndrome.
Authors: Mori S , Morisaki N , Saito Y , Yoshida S
Published: June 2011

Accumulation of lipid-laden foam cells of monocyte origin plays an important role in atherogenesis. Therefore, for determination of the mechanism of accelerated atherogenesis in Werner's syndrome, studies were carried out on the metabolism of acetylated low density lipoprotein (LDL) by monocyte-derived macrophages from patients with this syndrome. These macrophages showed abnormally high activities for degradation and uptake of 125I-acetylated LDL, incorporation of 14C-oleate into cellular cholesteryl ester in the presence of acetylated LDL, and accumulation of cholesteryl ester derived from internalized 3H-cholesteryl linoleate-labeled acetylated LDL. However, these macrophages showed normal binding of 125I-acetylated LDL. These results indicate that in monocyte-derived macrophages of patients with Werner's syndrome, the uptake, lysosomal hydrolysis, and re-esterification of free cholesterol are enhanced with no change in the receptor binding of acetylated LDL. As a result, these macrophages show increased accumulation of cholesteryl ester derived from acetylated LDL. This abnormal enhancement of cholesteryl ester accumulation may cause an accelerated conversion of macrophages to foam cells in Werner's syndrome.
Asymptomatic hyperglycemia is associated with lipid and lipoprotein changes favoring atherosclerosis.
Authors: Laakso M , Barrett-Connor E
Published: June 2011

We studied lipid and lipoprotein concentrations and their relationships to insulin level in 994 men and 1246 women ages 50 to 91 years in the upper middle-class community of Rancho Bernardo in southern California. Altogether, 593 men and 741 women had normal glucose tolerance, 240 men and 348 women, impaired glucose tolerance (IGT), 104 men and 117 women, newly diagnosed noninsulin-dependent diabetes (NIDDM), and 57 men and 40 women, previously diagnosed NIDDM. In women but not men, total cholesterol and low density lipoprotein were significantly higher in those with newly diagnosed NIDDM, compared to subjects with normal glucose tolerance. In both men and women, high density lipoprotein (HDL) cholesterol was significantly lower, and total triglyceride significantly higher, in subjects with IGT and NIDDM compared to those with normal glucose tolerance; these differences persisted after adjusting for age, body mass index, smoking, alcohol intake, and exercise level. Multiple linear-regression analyses showed that fasting insulin (but not 2-hour insulin) was significantly associated with low HDL cholesterol and high total triglycerides independently from other variables (age, body mass index, waist/hip ratio, alcohol intake, smoking, exercise, and 2-hour glucose). Overall, these results show that asymptomatic hyperglycemia (IGT, newly diagnosed NIDDM) is associated with lipid and lipoprotein changes favoring atherosclerosis and that fasting hyperinsulinemia (insulin resistance) is the most important factor associated with these lipid and lipoprotein abnormalities
Increase in endothelial cell density before artery enlargement in flow-loaded canine carotid artery.
Authors: Masuda H , Kawamura K , Tohda K , Shozawa T , Sageshima M , Kamiya A
Published: June 2011

To investigate the morphologic basis of blood flow-dependent adaptive vascular enlargement, we quantitated endothelial cell density, dimensions, and structure in canine carotid arteries that were flow-loaded for 4 weeks, i.e., just before the development of significant adaptive enlargement. Increased flow was produced in the right common carotid artery of seven adult beagle dogs by an arteriovenous shunt to the right external jugular vein. The left common carotid artery was used to produce sham-operated controls. Five additional animals were used to produce sham-shunted controls, and two dogs were used as nonoperated controls. The blood flow rate (BFR) and wall shear rate (WSR) were markedly increased immediately after anastomosis in the proximal segment of the shunted artery (BFR = 719 +/- 142 ml/min, WSR greater than 4127 +/- 1002/sec) and after 4 weeks (BFR = 628 +/- 157 ml/min, WSR greater than 2919 +/- 388/sec) compared to the same artery before anastomosis (BFR = 154 +/- 50 ml/min, WSR = 904 +/- 314/sec, p less than 0.01 x 10(-3) for both comparisons) and to the contralateral control artery after 4 weeks (BFR = 365 +/- 110 ml/min, WSR = 2136 +/- 876/sec, p less than 0.01 and p less than 0.05, respectively, compared to the shunted side). In the shunted artery, endothelial cell density was markedly increased (6.15 +/- 0.68 x 10(3) cells/mm2 compared to 3.33 +/- 0.70 x 10(3) cells/mm2 for the controls, p less than 0.001). Endothelial cells on the high flow side were markedly narrowed in both axial and circumferential directions, but were radially thickened; nuclei became prolate-spheroid in shape. On the control side, cells were relatively flat and thin. We conclude that elevated wall shear stress induces an early increase in endothelial cell number and that this increase precedes the development of significant blood flow-dependent vascular enlargement.