bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic aspects of arteriosclerosis.
Authors: Goldbourt U , Neufeld H N
Published: June 2011

This review discusses the genetic factors in the development of arteriosclerosis and coronary heart disease (CHD). In several studies, multivariate analysis of prospective mortality/morbidity data and angiographic findings have indicated that a family history of CHD contributed to CHD risk independently of the established risk factors. In addition, ethnic groups that differ in the prevalence and incidence of CHD also markedly differ in blood groups and protein-enzymatic markers. These or other genetic differences may affect CHD rates. Data from fraternal and identical twins, the source of some early genetic CHD findings, are reviewed. Genetic disorders of lipoprotein metabolism and transport, such as familial hypercholesterolemia, as well as other monogenic disorders are discussed. The role of apoprotein E polymorphism i other monogenic disorders are discussed. The role of apoprotein E polymorphism in determining plasma LDL variability among individuals is considered. Recombinant DNA technology, molecular cloning, and the identification of restriction fragment length polymorphisms are new tools for investigators who assess DNA polymorphism. Recent advances in that domain include: DNA polymorphisms affecting blood levels of apo A-I and A-II, association of a DNA insertion on chromosome 19 with severe premature atherosclerosis, and information concerning linkage of the genes for various apolipoproteins. In addition, the evidence for a major genetic component in diabetes mellitus and research into the genetic aspects of hypertension are reviewed. The male/female ratio in pathologically and epidemiologically assessed atherosclerosis may provide clues to the role of genetics. Early structural changes in the coronary artery intima are compatible with the ethnic and gender predilection. A key question in understanding underlying mechanisms in atherosclerosis is why coronary arteries are occluded in individuals whose other arterial systems are largely unaffected. The review concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on uncovering genetically determined differences in arterial wall response to blood flow. Subpopulations with different genetic risks may be identified, in which case universal preventive strategies might be replaced with specific ones.
Kinetic heterogeneity of low density lipoproteins in primary hypertriglyceridemia.
Authors: Vega G L , Grundy S M
Published: June 2011

The kinetics of two subfractions of low density lipoproteins (LDL) were examined in nine patients with primary hypertriglyceridemia. LDL was subjected to equilibrium ultracentrifugation, and three patterns of LDL subfractions were noted. The LDL of five patients with moderate hypertriglyceridemia (plasma triglycerides (TG) ranging from 333 to 580 mg/dl) appeared to contain two distinct subfractions. One was less dense and had a high TG content; the other was more dense and had a reduced content of all lipids, particularly cholesterol. Each subfraction was labeled separately and was reinjected into the patient. Of the two subfractions, the more dense LDL usually had a higher fractional catabolic rate (FCR), although the turnover rates of both subfractions for these hypertriglyceridemic patients were higher than normal. Two other patients with mild hypertriglyceridemia had only a single LDL after gradient equilibrium ultracentrifugation. This fraction was divided into less dense and more dense subfractions, and their FCR was determined. In both patients, turnover rates of the two subfractions were similar and both were in the normal range. Finally, two more patients with mildly elevated TG had a very dense LDL, besides having a single, less dense band. For both patients, the FCR for the less dense and very dense subfractions were similar, although the denser LDL had a greater fraction in the extravascular compartment. Thus, patients with primary moderate hypertriglyceridemia often have distinct subfractions that have different turnover rates. For patients with mild hypertriglyceridemia, the LDL is more homogeneous, and its subfractions are kinetically similar.
Partially reassembled high density lipoproteins. Effects on cholesterol flux, synthesis, and esterification in normal human skin fibroblasts.
Authors: Picardo M , Massey J B , Kuhn D E , Gotto A M , Gianturco S H , Pownall H J
Published: June 2011

The effects of a partially reassembled high density lipoprotein (PR-HDL) prepared by a detergent removal method on the cholesterol metabolism of fibroblasts has been tested under conditions of lipid depletion. The PR-HDL were composed of apolipoprotein A-I (1 mol) from human plasma HDL, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) 100 mol, and varying amounts of cholesterol. Below 15 mol%, the PR-HDL effected a net efflux of cholesterol from the fibroblasts; as a consequence, the activities of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A acyltransferase, respectively, were increased and decreased. Above 15 mol% cholesterol in the PR-HDL, net influx of cholesterol was observed and 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity was decreased, while acyl coenzyme A acyltransferase activity was increased. The uptake of several phosphatidylcholines, apo A-I, and cholesterol were measured as a function of time. The rates of lipid transfer to the cells decreased with increasing hydrophobicity of the transferring lipid. By contrast, in parallel experiments a relatively small quantity of 125I apo A-I was associated with the cells. Our results suggest that a component of lipid transfer from PR-HDL to fibroblasts occurs via monomeric transfer through the aqueous phase that is independent of apo A-I binding.
Peanut oil reduces diet-induced atherosclerosis in cynomolgus monkeys.
Authors: Alderson L M , Hayes K C , Nicolosi R J
Published: June 2011

The atherogenicity of dietary peanut oil (PO) was examined in cynomolgus monkeys fed semipurified diets for 15 months. Four groups of six monkeys were fed diets containing 0.22 mg/kcal (0.1%) cholesterol and 0%, 5%, 10%, or 20% PO. An additional group was fed 2.0% cholesterol and 20% PO to serve as a literature control. Increasing the concentration of PO in the diet was associated with significant decreases in total plasma cholesterol (p less than 0.05) and the total/HDL cholesterol ratio (p less than 0.05) and an increase in the terminal HDL cholesterol concentration (p less than 0.05). Intimal thickness and composition were determined from cross sections of the thoracic aorta and the iliac and coronary arteries. Increasing dietary PO was associated with decreases in thickness (p less than 0.005), lipid (p less than 0.001), and smooth muscle cells (p less than 0.005) in the aortic intima. Aortic intimal lipid was positively correlated with the ratio of total to HDL cholesterol (r2 = 0.78, p less than 0.05). Monkeys fed 2.0% cholesterol and 20% PO revealed extensive atherosclerosis in all three arterial sites compared with those of any other group. Whereas the dietary fat effect was most demonstrable in the aorta, dietary cholesterol had a greater effect on the iliac and coronary arteries than it did on the aorta. Under these circumstances, dietary PO was not atherogenic in cynomolgus monkeys when fed with a concentration of cholesterol equivalent to that consumed by humans.
Modulation of proteoglycan metabolism by aortic smooth muscle cells grown on collagen gels.
Authors: Lark M W , Wight T N
Published: June 2011

The nature of the extracellular matrix may influence the types and amounts of proteoglycans synthesized by arterial smooth muscle cells. To determine if collagen modulates proteoglycan metabolism by these cells, arterial smooth muscle cells derived from aortic explants of the pigtail monkey (Macaca nemestrina) were cultured on both tissue culture plastic and hydrated type I collagen gels for 7 days. Cells were radiolabeled with Na2[35S]O4 during the final 48 hours of the growth period, and proteoglycans were extracted from the culture medium and cell layer by using 4 M guanidine hydrochloride in the presence of protease inhibitors. Cultures on collagen accumulated approximately 40% less [35S]O4 = -radiolabeled proteoglycan when compared to cultures on plastic. However, cells on collagen accumulated approximately 50% of their newly synthesized proteoglycan within the cell layer, while cells on plastic deposited less than 20% of their total radiolabeled proteoglycan in this culture compartment. Pulse-chase analysis indicated that the elevated accumulation of proteoglycan observed in the cell layer of collagen cultures was due, at least in part, to inhibition of turnover of these molecules. Cells on both collagen and plastic synthesized a large chondroitin sulfate proteoglycan which was secreted into the medium and deposited within the cell layer. On the other hand, cells on collagen synthesized a smaller iduronic acid-rich dermatan sulfate proteoglycan which was deposited only within the collagen gel and not secreted into the medium. By comparison, cells grown on plastic synthesized both a small glucuronic acid-rich dermatan sulfate proteoglycan which was secreted into the medium as well as an iduronic acid-rich dermatan sulfate which was present in the cell layer. Unlike the cell layer-derived dermatan sulfate proteoglycan isolated from the collagen gels, the majority of the cell layer-derived dermatan sulfate from cells on plastic was insensitive to papain treatment and thus identified as free glycosaminoglycan chains. Analysis of the total radiolabeled proteoglycans isolated under the two culture conditions indicated that cultures grown on collagen accumulate less chondroitin sulfate proteoglycan and heparan sulfate proteoglycan but over twice as much iduronic acid-rich dermatan sulfate proteoglycan. This culture system is offered as a model to determine the mechanisms by which collagen may in part regulate the metabolism of proteoglycans by arterial smooth muscle cells.
Population-based study of glycosylated hemoglobin, lipids, and lipoproteins in nondiabetic adults.
Authors: Barrett-Connor E , Criqui M H , Witztum J L , Philippi T , Zettner A
Published: June 2011

Glycosylated hemoglobin levels reflect glucose homeostasis over the preceding months. Many investigators have reported levels of glycosylated hemoglobin in diabetics and have noted a strong correlation of these levels with lipids and lipoproteins, but not with HDL cholesterol. We report here the first population-based study of the predominant fraction of glycosylated hemoglobin, HbA1, and its correlates in nondiabetics. In 558 euglycemic adults (fasting plasma glucose less than 140 mg/dl) aged 40 to 79 years who had no history of diabetes, HbA1 was normally distributed, was unrelated to age, and was correlated with fasting plasma glucose in men and women and with obesity in women. After adjusting for age and obesity, HbA1 was significantly correlated with total plasma cholesterol and LDL cholesterol in both sexes and with total plasma triglyceride and VLDL cholesterol in men. HDL cholesterol was not significantly associated with HbA1 in men or women. These associations are similar, although weaker, than those reported in most studies of diabetics. The finding that the association of glycosylated hemoglobin with lipids and lipoproteins extends throughout the normal range of blood sugar suggests that this association may be relevant to both the excess risk of ischemic heart disease in diabetics and in nondiabetics with higher levels of fasting plasma glucose.
Alteration of high density lipoprotein subfractions of nonhuman primates fed fish-oil diets. Selective lowering of HDL subfractions of intermediate size and density.
Authors: Parks J S , Martin J A , Sonbert B L , Bullock B C
Published: June 2011

Two groups of adult male African green grivet monkeys (12 animals in each group) were fed atherogenic diets containing 40% of total calories as fat with half of the fat calories derived from lard or menhaden oil and 0.8 mg cholesterol/kcal for a period of 10 months to ascertain the effect of such diets on lipoprotein concentrations, composition, and distribution. After 8 months on this diet, the animals' lipoproteins were isolated from their plasma by ultracentrifugation and agarose column chromatography, and these were characterized chemically. Compared with the lard-fed group, the menhaden oil-fed animals had significantly lower total plasma cholesterol (decreases 33%), HDL cholesterol (decreases 33%) and apo A-I (decreases 30%) concentrations and LDL molecular weights (decreases 15%). Although the fish-oil diets resulted in an average similar reduction of LDL cholesterol concentrations (decreases 34%), the decrease was not statistically significant. The lipid and apoprotein compositions of plasma LDL and HDL were similar between the two groups of animals. The distribution of HDL subfractions was determined by gradient gel electrophoresis and density gradient ultracentrifugation. The fish-oil group had a significant reduction in protein (decreases 46%) of HDL subfractions of intermediate size (80 to 88 A) compared to the lard-fed group. By density gradient ultracentrifugation, there was a 35% to 40% lower concentration of protein in the d = 1.10-1.13 g/ml subfraction of fish-oil-fed monkeys. Thus, feeding fish oil to nonhuman primates results in a selective decrease in the concentration of HDL subfractions of intermediate size and density compared to lard-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Mass transport, atherogenesis, and risk.
Authors: Fry D L
Published: June 2011

If the local chemically-active interstitial concentration (chemical activity) of a particular atherogenic molecule (atherogen) is considered to be one of the fundamental driving forces in a system of reactions that produces an associated local atherogenic change, then the chemical activity may be used as a measure of the potential for lesion development or local "risk." A model of steady-state, combined, diffusive and convective transport of an assumed atherogen across a multilayered arterial wall was used to illustrate mechanisms by which transport processes interact with tissue barriers to determine the transmural (x axis) chemical activity distributions [a(x), mol cm-3]. The model was used to evaluate the effects of increased endothelial gap fractional area (increased endothelial permeability), elevated blood pressure, elevated serum concentration of the atherogen, internal elastica fenestration, and preexisting intimal thickening on a(x). It was found that sites along the arterial tree that are characterized by "mild" increases in endothelial gap fractional area and concomitant subjacent interstitial sieving of the atherogen developed high a(x), in some cases much higher than that (a0) of the blood, and therefore were at high risk even in the absence of other risk factors. Moreover, the risk at such sites was dramatically increased with hypertension and/or elevated serum atherogen concentration and/or preexisting intimal thickening. However, if either condition, i.e., opened endothelial intercellular junctions or subjacent interstitial sieving, was absent, these other risk factors were ineffective. Finally, the response of the model was shown to be consistent with a variety of well-known, as well as puzzling, observations suggesting that transport processes may play roles in determining both the architecture of the atherosclerotic lesion and its rate of development.
Mapping of human apolipoprotein B antigenic determinants.
Authors: Marcel Y L , Innerarity T L , Spilman C , Mahley R W , Protter A A , Milne R W
Published: June 2011

A minimum of 16 epitopes which provide a group of topographical markers to study the conformation of apolipoprotein (apo) B have been mapped in relation to elements of the sequence of apo B-100. Six of these epitopes are identified by monoclonal antibodies (Mabs) directed against low density lipoprotein (LDL) apo B, while at least 10 others react with Mabs obtained by immunization with delipidated and solubilized apo B. Five epitopes which are also expressed on apo B-48 have been assigned to the thrombolytic fragment T4 on the N-terminal side of apo B-100. None of these five epitopes requires the presence of lipids for its expression, suggesting that the conformation of the T4 region of apo B is more dependent on peptide-chain interactions than on peptide-lipid interactions. Four distinct epitopes have been assigned to the median thrombolytic fragment T3 of apo B-100, all of which require the presence of lipids for their expression; those epitopes closer to the C-terminus of T3 require specific interaction with cholesteryl esters. The same lipid dependence also characterizes a cluster of epitopes mapped to the N-terminal region of fragment T2. The epitopes that are close to the T2/T3 cleavage site and depend on the presence of cholesteryl esters for their expression are also those that react with the Mabs that inhibit the binding of LDL to its receptor. Therefore this region, which in addition contains two sequences with structural homology to the apo E receptor binding domain, probably constitutes a physiologically important receptor binding site for apo B. Finally, four other distinct epitopes which do not require the presence of lipids for their expression have been mapped on T2. In conclusion, the present report presents evidence that the immunochemical analogy of apo B-48 and apo B-100 is on the N-terminal half of apo B-100, whereas the apo B receptor binding domain is localized on the C-terminal half of apo B-100 close to the T2/T3 cleavage site.
Oxygen consumption in aortic tissue from rabbits with diet-induced atherosclerosis.
Authors: Björnheden T , Bondjers G
Published: June 2011

The inner parts of the arterial wall depend upon diffusion for nutrition and oxygenation. During the atherosclerotic process, increased intimal thickness leads to impaired diffusion, and at the same time the oxygen requirements increase. On this basis it has been suggested that the balance between the supply and demand of oxygen in the arterial wall may be important for the fate of the initiated lesion. In the first part of the present study, the oxygen consumption was measured during perfusion in aortic intima-media segments from cholesterol-fed rabbits. The results indicated that the oxygen consumption per DNA increased with increasing degree of atherosclerotic involvement up to a certain level. For more diseased aortas, however, the oxygen consumption decreased again. In the second part of the study, the oxygen consumption was measured in foam cell and smooth muscle cell fractions isolated from rabbit aortic intima-media. These measurements indicated that the oxygen consumption of isolated foam cells was three times higher than that of isolated smooth muscle cells. It is proposed in the study that the increased oxygen consumption of the less diseased aortas reflected an increased proportion of foam cells in the arterial wall. As the lesions grow and the number of foam cells in the intima increases, the available diffusion capacity for oxygen and nutrients to deeper parts of the lesion may become insufficient, leading to the observed decrease in cellular oxygen consumption of the more diseased samples. Hypoxic cell damage and further tissue reactions may occur and the healing of the initiated lesion may be endangered.
Gender and baboon aortic steroid hormone receptors.
Authors: Lin A L , Gonzalez R , Carey K D , Shain S A
Published: June 2011

To examine the potential of steroid hormones to serve as putative regulators of aortic cell function, we defined hormone receptor content and distribution in intact baboons. Total androgen receptor content in baboon aortic arch, thoracic arch, and abdominal aorta of young mature males was indistinguishable from that of proestrus females. However, 30% to 40% of male aortic androgen receptors were in the nuclear fraction, whereas all aortic androgen receptors of proestrus females were in the cytoplasmic fraction. Cytoplasmic fraction estrogen receptor content of aortic arch and thoracic aorta of intact males was indistinguishable from that of proestrus females. However, cytoplasmic fraction estrogen receptor content of abdominal aorta of proestrus females was significantly greater than that of males. Nuclear fraction estrogen receptors were not detectable in either male or proestrus female baboon aortas. To assess effects of endogenous estrogen on aortic progesterone receptor content, we quantified cytoplasmic fraction progesterone receptors and found that content of proestrus female aortic arch was not significantly different from that of males. However, cytoplasmic fraction progesterone receptor content of thoracic and abdominal aorta of proestrus females was significantly higher than that of males. To determine whether differences in aortic receptor content or distribution were associated with changes in aortic cell function, we quantified the activity of two enzymes of glycosaminoglycan metabolism. Aortic beta-glucuronidase activity was not different in male or proestrus female baboons.(ABSTRACT TRUNCATED AT 250 WORDS)
High density lipoprotein free cholesterol and other lipids in coronary heart disease.
Authors: Moshides J S
Published: June 2011

The cholesterol and choline-containing phospholipid fractions of high density lipoproteins (HDL) were determined in healthy males and in male patients with coronary heart disease (CHD) to ascertain which HDL parameter or combined parameters possess the greatest discriminative power. The free cholesterol fraction (HDL-fc) was found to be the most significant discriminator between controls and males with CHD, the mean levels (+/- SEM) being 6.6 (+/- 0.9) and 4.4 (+/- 0.6) mg/dl, respectively. Classification of CHD patients and controls using one-variable discriminant function analysis (DFA) yielded an error rate of 27% for plasma HDL-fc. Two-variable DFA using both the HDL esterified cholesterol levels and the HDL-fc levels of controls and patients reduced the error rate to 11%. The results obtained in this study indicate a possible role for HDL-fc as a predictor of CHD risk.
Divergent levels of high density lipoprotein cholesterol and apolipoprotein A-I in children. The Bogalusa Heart Study.
Authors: Freedman D S , Srinivasan S R , Webber L S , Berenson G S
Published: June 2011

Clinical studies indicate that levels of apolipoprotein A-I (apo A-I), the major protein moiety of the high density lipoprotein (HDL) particle, may provide more information concerning the risk of future cardiovascular disease than do levels of HDL cholesterol (HDL-C). Therefore, the relationship of HDL-C to apo A-I levels was examined in a biracial sample of 2849 5- to 17-year-olds. The mean HDL-C to apo A-I ratio, a measure of HDL composition, was 0.42. However, marked interindividual variation was found: HDL-C/apo A-I levels varied from 0.27 (10th percentile) to 0.57 (90th percentile). Furthermore, only 26% of the variation in HDL-C levels was explained by concomitant variation in apo A-I. Increasing levels of triglyceride (and very low density lipoprotein cholesterol) were related to decreases in both the HDL-C/apo A-I ratio and the magnitude of the correlation between HDL-C and apo A-I. Low density lipoprotein cholesterol, race, and age were also related to the HDL-C/apo A-I ratio, but influenced HDL composition less strongly than did triglyceride levels. These observations may be explained by the bidirectional transfer of cholesteryl esters and triglycerides between HDL and triglyceride-rich lipoproteins. The current study documents the influence of triglyceride levels on HDL composition in a general population of children and adolescents, and emphasizes the interrelationships between the various lipid and lipoprotein fractions.
Accumulation of native and methylated low density lipoproteins by healing rabbit arterial wall.
Authors: Fischman A J , Lees A M , Lees R S , Barlai-Kovach M , Strauss H W
Published: June 2011

To determine whether healing arterial wall accumulation of low density lipoproteins (LDL) is mediated by the high affinity LDL receptor, normocholesterolemic rabbits were injected with 125I-LDL, 99mTc-LDL, or the reductively methylated analogs of these compounds (125I-MeLDL, 99mTc-MeLDL), 1 month after balloon catheter deendothelialization of the abdominal aorta. If the mechanism of accumulation requires interaction with the LDL receptor, reductively methylated lipoproteins which do not bind to the receptor should not accumulate in healing arterial wall. Twenty-four hours after injection of labelled lipoproteins, each animal was injected with Evans blue dye, in order to distinguish reendothelialized from deendothelialized aorta. One hour after dye injection, the aorta was fixed, removed, divided into abdominal (ballooned) and thoracic (unballooned) regions and counted. For all lipoprotein preparations, there were three to four times as many counts in the abdominal as in the thoracic aorta. En face autoradiographs were made of the aortas that had been exposed to 125I-labelled lipoproteins. In the autoradiographs, the areas of the lowest activity corresponded to the centers of healing endothelial islands. The most intense radioactivity for both lipoproteins occurred in the region of the leading edge of the endothelial islands where active endothelial regeneration was in progress. The overall distribution of native and MeLDL accumulation was the same. The results suggest that low density lipoproteins are accumulated in areas of active endothelial regeneration by a mechanism that does not involve the high affinity LDL receptor.
Enhanced accumulation and turnover of esterified cholesterol in injured rabbit aorta.
Authors: Schwenke D C , Zilversmit D B
Published: June 2011

Arterial injury exacerbates experimental atherogenesis. This report evaluates cholesteryl ester influx and loss during the first 5 days after arterial injury. Selected areas of aortas from rabbits made hypercholesterolemic by 12 to 16 days of cholesterol feeding were injured with a balloon catheter. This allowed measurements and a relatively precise comparison of cholesterol and cholesteryl ester influx into the uninjured and injured arterial wall within the same animal. The animals received oral doses of 3H- or 14C-cholesterol either just before injury or 1 day later. Most animals were given the other isotope of cholesterol 1 day before sacrifice, which took place 2 to 5 days after injury. Measurement of accumulated labelled esterified cholesterol within the same animal during two different time periods allowed the estimation of total influx and fractional loss of entered esterified cholesterol within the artery. Between 2 and 5 days after injury, total influx into areas of injured artery averaged 30 to 60 times the total influx into the adjacent uninjured areas. By the fifth day after injury, the esterified cholesterol content was about 10 times greater in injured areas than in adjacent, uninjured areas. The nonesterified cholesterol content of injured areas was about 70% greater than that of adjacent noninjured areas. Total influx and fractional loss of arterial cholesteryl ester calculated from radioactivity data could account for 117 +/- 6 (mean +/- SEM) percent of the cholesteryl ester mass that accumulated during the interval from injury to sacrifice. The total influx rates and daily increments in cholesteryl ester content of injured areas were positively related.
Metabolism of human intermediate and very low density lipoprotein subfractions from normal and dysbetalipoproteinemic plasma. In vivo studies in rat.
Authors: Musliner T A , McVicker K M , Iosefa J F , Krauss R M
Published: June 2011

Subfractions of radioiodinated d less than 1.019 g/ml lipoproteins were isolated by nonequilibrium density gradient ultracentrifugation (DGU) from normal and dysbetalipoproteinemic human plasma and were injected into rats. Size and density (d) of lipoprotein products formed over 8 hours were assessed by gradient gel electrophoresis and equilibrium DGU, respectively. Subfractions containing a subspecies of very low density lipoproteins (VLDL) of particle diameter greater than 350 A were cleared rapidly from the plasma and formed only small amounts of low density lipoproteins (LDL). Fractions containing VLDL subspecies of smaller diameter (300 to 350 A) were cleared much more slowly, and formed greater amounts of a discrete LDL product with the characteristics of human LDL-II (peak particle diameter 255 to 265 A, d = 1.030 to 1.040 g/ml). A similar LDL product was formed from subfractions containing intermediate density lipoproteins (IDL). Cholesterol-enriched subspecies within the smaller, denser portion of the IDL spectrum, however, yielded two additional products. One had size and density characteristic of the major human LDL-I subclass reported previously (265 to 275 A, d = 1.025 to 1.030 g/ml), while the other was yet larger (275 to 285 A) and overlapped normal IDL in size and density. In dysbetalipoproteinemic plasma, the metabolic precursors of the largest product were shifted from the IDL to the small VLDL (beta-VLDL) particle distribution. Since beta-VLDL are known to predispose to accelerated atherosclerosis in dysbetalipoproteinemia, it may be that metabolically homologous cholesterol-enriched IDL subspecies in other subjects have similar atherogenic properties.
Inheritance of high density lipoprotein and lipoprotein lipase and hepatic lipase activity.
Authors: Kuusi T , Kesäniemi Y A , Vuoristo M , Miettinen T A , Koskenvuo M
Published: June 2011

The role of genetic and environmental factors in the regulation of plasma high density lipoprotein (HDL) was estimated in 17 monozygotic (MZ) and 18 dizygotic (DZ) male twins randomly selected from the Finnish Twin Cohort Study. In addition to HDL cholesterol, we determined the HDL subfractions, HDL2 and HDL3, and the major HDL apoproteins (apo) A-I and A-II. The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were also assayed from postheparin plasma to get information on their possible contribution to the heritability of HDL. Evidence for the genetic component in the regulation of plasma HDL received support from the heritability estimate of 0.34. The different heritability estimates of HDL2 and HDL3 (h2 of 0.56 and less than 0, respectively) support the idea that the HDL subfraction distribution might be important in the genetic regulation of plasma HDL level. This also received support from the heritability of apo A-I (h2 = 0.66), mainly varying in HDL2, and the lack of it in apo A-II, found mainly in HDL3. These conclusions were strengthened by standardizing the data with relative ponderosity. Postheparin plasma HL activity had a high pairwise correlation coefficient in the MZ twins (r = 0.80, p less than 0.001), whereas LPL displayed no within-pair correlation. Neither of the lipolytic enzymes, LPL or HL, showed any correlation in the DZ twins. Therefore, it is suggested that part of the genetic regulation of the HDL and its subfraction distribution might be mediated through the activity of HL.
Apolipoprotein A-IMilano. Correlation between high density lipoprotein subclass distribution and triglyceridemia.
Authors: Franceschini G , Calabresi L , Tosi C , Sirtori C R , Fragiacomo C , Noseda G , Gong E , Blanche P , Nichols A V
Published: June 2011

Carriers of the apolipoprotein A-IMilano (apo A-IM) variant represent a selected group of subjects showing low levels of high density lipoprotein (HDL), variable hypertriglyceridemia, and low prevalence of atherosclerotic vascular disease. The distribution of HDL subfractions and the correlation with abnormalities in triglyceride transport were determined in these subjects. Sera from 24 apo A-IM carriers (A-IM+ and from age- and sex-matched normolipidemic controls (A-IM-) were analyzed by rate zonal ultracentrifugation. The A-IM+ subjects showed a marked decrease of HDL3 mass with reduced flotation rates and major compositional alterations; the HDL2 were nearly absent. The HDL subclasses from 10 A-IM+ subjects were resolved according to particle size by gradient gel electrophoresis (GGE). The HDL patterns detected in the carriers were unique in exhibiting a distinct peak in the (HDL3b)gge interval, undetectable in the controls. Three patterns reflecting the relative contributions of smaller (HDL3b)gge and larger (HDL3a)gge particles could be distinguished in the carriers, and these were clearly related to different triglyceride and HDL cholesterol levels in plasma. These findings in a highly selected group of subjects with generally low HDL levels and quite variable triglyceridemia confirmed the existence of relationships between alterations in triglyceride transport and abnormalities in the HDL subclass distribution, possibly reflecting the variable atherosclerotic risk in hypertriglyceridemic subjects.
Influx and cellular degradation of low density lipoproteins in rabbit aorta determined in an in vitro perfusion system.
Authors: Wiklund O , Björnheden T , Olofsson S O , Bondjers G
Published: June 2011

The accumulation of 125I-low density lipoprotein (LDL) into normal and atherosclerotic arterial tissue and cellular uptake in arterial cells were studied in an in vitro perfusion system for rabbit aorta. The accumulation of 125I-LDL in normal tissue could be fitted to an inverse exponential function with an initial influx rate of 1.39 nl/mg wet weight/hour and an equilibration volume of about 2% of the tissue volume. The influx rate into atherosclerotic plaques was about 10 times faster and the equilibration volume, 50 times higher. In atherosclerotic tissue there was a steep concentration gradient between the plaque and the underlying media. The accumulation of 125I-LDL in the media under plaque and in normal tissue adjacent to plaques was similar to that seen in normal tissue. For studies of cellular uptake of LDL a trace label, 125I-tyramine-cellobiose (TC), was used. Normal or atherosclerotic rabbit aorta was perfused in vitro with medium containing 125I-TC-LDL. After perfusion the tissue was digested and the cells were isolated by density gradient centrifugation. Two main cell fractions with characteristics of smooth muscle cells and foam cells, respectively, were obtained. A 70-fold higher uptake was seen in the foam cells. In conclusion, these studies suggest a higher influx rate into atherosclerotic plaques, as well as a high LDL concentration in the plaque, compared with normal tissue or underlying media. We suggest that most of the cellular uptake of LDL in the arterial wall is caused by the foam cells.
Effect of chronic low dose aspirin on platelet and vascular eicosanoid metabolism in nonhuman primates (Macaca fascicularis).
Authors: Jakubowski J A , Bush H L , Vaillancourt R , Deykin D
Published: June 2011

It has been suggested that inhibition of platelet cyclooxygenase by chronic low dose aspirin may spare vascular prostacyclin production. Conventional doses of aspirin (greater than 5 mg/kg) have been shown to inhibit the generation of both thromboxane A2 and prostacyclin. Low dose aspirin inhibits prostacyclin production by excised human venous tissue, thus questioning the selectivity of such regimens. However, many clinical and surgical conditions requiring platelet inhibition involve the arterial system. We have studied the effects of various aspirin regimens on platelet, venous, and arterial cyclooxygenase activity in a nonhuman primate (Macaca fascicularis). We determined the lowest chronic dose of oral aspirin required to effectively inhibit platelet cyclooxygenase and aggregation to be 1 mg/kg. After 14 days of 0, 1, or 2 mg/kg aspirin, intact veins and arteries were surgically removed and perfused, and luminal prostacyclin (6-keto-PGF1 alpha) generation was assessed. Levels of 6-keto-PGF1 alpha in venous perfusates were reduced by 89% and 86% (p less than 0.05) after 1 and 2 mg/kg, respectively. Arterial 6-keto-PGF1 alpha levels were unchanged by 1 mg/kg aspirin, but after 2 mg/kg were reduced by 66% (p less than 0.05). Preferential inhibition of platelet over arterial cyclooxygenase is thus achievable, but only over a narrow dose range.
Total cholesterol and high density lipoprotein cholesterol levels in populations differing in fat and carbohydrate intake.
Authors: Knuiman J T , West C E , Katan M B , Hautvast J G
Published: June 2011

This paper reviews epidemiological studies on the relationship between diet and high density lipoproteins (HDL), with emphasis on the authors' studies of boys and men from different countries and with different dietary habits. Sera were collected from boys (ages 7 to 9 years) and men (ages 33 to 48 years) in 20 countries, and these were analyzed in one standardized laboratory. In boys, total and HDL cholesterol changed in parallel, from low values in populations in developing countries with low-fat, high-carbohydrate diets to high values in affluent populations. The correlation between HDL and total cholesterol was 0.90 (n = 16 populations). A similar trend was seen in groups of vegetarian and omnivorous boys within one region. Detailed analyses of individual diets of boys in five countries showed a negative relation between carbohydrate intake and HDL cholesterol both for group means (r = -0.99, n = 5) and for individual boys within one country (r = -0.26 to 0.04, n = 109 to 133 boys per country). In these boys, differences in obesity and physical activity were slight, and unrelated to differences in HDL. Total cholesterol rose with saturated fat intake (r = 0.87 for five population means; r = 0.07 to 0.26 within population groups). In adult men, total and HDL cholesterol also tended to rise simultaneously with affluence. However, the relation was much weaker (r = 0.60, n = 13 population groups).(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoprotein E polymorphism and atherosclerosis.
Authors: Davignon J , Gregg R E , Sing C F
Published: June 2011

The apo E locus contributes to determining the variation in plasma cholesterol levels of healthy and diseased populations. It also influences the expression of hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a complex multifactorial interaction. There is evidence that the presence of apo E2 is protective, whereas that of apo E4 predisposes to coronary artery disease. The burden of proof, however, lies on future, well-designed clinical trials and prospective studies. The study of the biological significance of the apo E polymorphism in humans has emphasized the importance of gene-gene and gene-environment interactions in the pathogenesis of hyperlipidemia and atherosclerosis. The apo E polymorphism involves the coding region of the apo E gene and results in alterations of the gene product which, in turn, either directly or secondarily affect the metabolic fate of the lipoprotein particles. Rapid advances in knowledge over the last decade have provided a metabolic explanation for the observation of the opposite effects of the epsilon 4 and the epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity which results in delayed clearance of apo E2-bearing lipoprotein particles from plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is degraded more rapidly than apo E3, and may enhance the catabolism of E4-bearing particles, leading to other alterations in lipoprotein metabolism which result in elevated levels of LDL. In view of the significant opposite impacts of the epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is evident that determination of the apo E phenotype will become a useful adjunct to the assessment of the cardiovascular risk profile of an individual. In addition, the relationship between the epsilon 2 allele and type III hyperlipoproteinemia provides a valuable model for the study of complex genetic interactions in the pathogenesis of hyperlipidemia. The further study of apo E and its interactions shows great promise for a deeper comprehension of the pathogenesis of atherosclerosis.
Prostacyclin, thromboxane A2, and prostaglandin E2 formation in atherosclerotic human carotid artery.
Authors: Rush D S , Kerstein M D , Bellan J A , Knoop S M , Mayeux P R , Hyman A L , Kadowitz P J , McNamara D B
Published: June 2011

Prostaglandin (PG) formation in 16 atherosclerotic human carotid endarterectomy specimens was compared systematically with that of normal carotid artery from seven white pigs and six rhesus monkeys. Prostacyclin (PGI2) formation (picomoles 6-keto-PGF1a/2 min/100 micrograms homogenate protein plus 2 mM glutathione [GSH]) of nonatheromatous intima adjacent proximal (276 +/- 32, mean +/- SEM) or distal (271 +/- 14) to carotid plaque was comparable to that of normal carotid artery from white pig (272 +/- 25, NS) and rhesus monkey (219 +/- 41, NS), and was greater than stenotic intima (156 +/- 17, p less than 0.01), subintimal plaque (168 +/- 14, p less than 0.01), and ulceration (65 +/- 16, p less than 0.01). GSH modulated PGI2 synthesis in all carotid specimens except areas of ulceration (p less than 0.05), but did not restore PGI2 formation in atheromatous fractions to basal level. No detectable arterial thromboxane A2 (TXA2) formation or GSH-dependent PGE2 isomerase activity was observed. The decrement in atherosclerotic carotid artery PGI2 formation was focal (confined to the plaque) and may have been related to loss of effective GSH modulation. These conditions could contribute to a localized imbalance between arterial PGI2 and platelet TXA2 with adverse vascular thromboregulatory consequences.
Body fat distribution, plasma lipids, and lipoproteins.
Authors: Anderson A J , Sobocinski K A , Freedman D S , Barboriak J J , Rimm A A , Gruchow H W
Published: June 2011

The relation of body fat distribution as measured by the ratio of waist to hip circumferences (WHR) to plasma levels of lipids and lipoproteins was studied in 713 men and 520 women who were employed by two Milwaukee companies. Quetelet index (kg/m2), waist girth, hip girth, and WHR were each positively related to levels of total cholesterol, triglycerides, apolipoprotein B, and the ratio of total to high density lipoprotein (HDL) cholesterol. In addition, the anthropometric measures were inversely associated with levels of HDL cholesterol. (Controlling for age, alcohol intake, exercise level, current smoking status, and oral contraceptive use only slightly reduced the strength of the correlations.) In addition, WHR and Quetelet Index were independently related to lipid and lipoprotein levels, and the magnitudes of the associations were roughly equivalent. For example, the mean (covariate-adjusted) triglyceride level among men in the upper tertile of the Quetelet Index was 37 mg/dl higher than for men in the lower tertile of the Quetelet Index; the corresponding difference according to WHR tertiles (upper to lower) was 39 mg/dl (p less than 0.01 for both effects). These findings indicate that in healthy men and women a less favorable lipid and lipoprotein profile is associated with elevated levels of both Quetelet Index and WHR.
Metabolism of canine beta-very low density lipoproteins in normal and cholesterol-fed dogs.
Authors: Fainaru M , Funke H , Boyles J K , Ludwig E H , Innerarity T L , Mahley R W
Published: June 2011

Cholesteryl ester-rich beta-very low density lipoproteins (beta-VLDL) are beta-migrating lipoproteins that accumulate in the plasma of cholesterol-fed animals and of patients with type III hyperlipoproteinemia. There are two distinct fractions: fraction I beta-VLDL are chylomicron remnants of intestinal origin, and fraction II beta-VLDL are cholesterol-rich VLDL of hepatic origin. The liver rapidly clears fraction I beta-VLDL from the plasma of both normal and cholesterol-fed dogs. The liver also clears fraction II beta-VLDL rapidly and efficiently from the plasma of normal dogs by receptor-mediated uptake. In cholesterol-fed dogs the clearance is biphasic: an initial rapid die-away of about 30% to 40% of the injected dose within 5 minutes, followed by a slow clearance of plasma radioactivity (a half-life of more than 20 hours). The rapid, initial phase of fraction II beta-VLDL clearance appears to be related to sequestration of the lipoproteins presumably on endothelial cells and is apparently associated with lipolytic processing. Treatment of the fraction II beta-VLDL with lipoprotein lipase abolishes this rapid phase. In the cholesterol-fed dog, the slow, late phase of clearance corresponds to the conversion of fraction II beta-VLDL to the smaller, denser intermediate and low density lipoproteins (IDL and LDL), which are slowly cleared from the plasma. It is concluded that fraction II beta-VLDL are catabolized in the normal dog by rapid uptake mediated at least in part by the apo B,E(LDL) receptor of hepatic parenchymal cells. In cholesterol-fed dogs, in which these receptors are markedly down-regulated, fraction II beta-VLDL are apparently initially bound to endothelial cells and converted to IDL and LDL by lipolytic processing.
Effect of dextran 40 on endothelial binding and vesicle loading of ferritin in rabbit aorta.
Authors: Baldwin A L , Chien S
Published: June 2011

The effects of dextran 40 on endothelial binding and vesicle loading of cationized (CF, pl greater than 9.0) and anionic (AF, pl = 3.8 to 4.2) ferritins were investigated in the rabbit aorta. After two minutes of in situ perfusion, both ferritin species entered luminal vesicles and bound to the luminal endothelial membrane with a high surface density at vesicle necks. With CF, the presence of 5% dextran 40 did not change the fraction of vesicles loaded, the number of particles per vesicle, or the average density of particles bound to the luminal membrane, but did reduce the average density of particles adhering to vesicle necks. With AF, dextran 40 increased the percentage of vesicles filled, the average number of particles per loaded vesicle, the membrane particle density, the percentage of loaded vesicle necks, and the average density of particles adhering to vesicle necks. Application of gel chromatography and electrophoresis and determination of carbohydrates in the ferritin and dextran perfusates by the anthrone method after precipitation of the ferritin demonstrated that the dextran and ferritin did not conjugate. We hypothesize that the dextran binds to the endothelial membrane and increases its affinity to AF possibly by shielding negatively charged sites and that it binds in such a way as to offer little steric hindrance to AF particles entering vesicles.
New variant of low density lipoprotein receptor gene. FH-Tonami.
Authors: Kajinami K , Mabuchi H , Itoh H , Michishita I , Takeda M , Wakasugi T , Koizumi J , Takeda R
Published: June 2011

A new variant of the low density lipoprotein receptor (LDLR) gene was ascertained through Southern blotting analysis of LDLR genes of 35 unrelated Japanese patients with heterozygous familial hypercholesterolemia (FH). This mutant gene had a 6 kilobase deletion which had eliminated only exon 15, an exon that encodes the O-linked sugar domain. The mutation was recognized in two patients with heterozygous FH. We refer to these patients as 'FH-Tonami', since they were both born in the Japanese district of Tonami. Although there is no evidence of a relation between families, the possibility of a common ancestor with FH does exist. Neonatal diagnosis of FH in two fetuses from one family was possible through analyses of their LDLR genes in cord blood samples at delivery.