bluuebunny/crossref_metadata_2025 huggingface dataset:
Very low density lipoproteins promote triglyceride accumulation in macrophages.
Authors: Bates S R , Murphy P L , Feng Z C , Kanazawa T , Getz G S
Published: June 2011

Incubation of mouse peritoneal macrophages with very low density lipoproteins (VLDL) from normal rats or rhesus monkeys markedly increased the levels of intracellular triglycerides by 10- to 56-fold and was accompanied by the production of oil red O positive vacuoles. The stimulation of triglyceride accumulation in macrophages was time- and concentration-dependent and was specific for VLDL. Three possible mechanisms for the VLDL-stimulated triglyceride accumulation in macrophages were explored: receptor-mediated uptake, action of lipoprotein lipase, and phagocytosis. Macrophage uptake and degradation of 125I-monkey and rat VLDL demonstrated saturable and nonsaturable components. Uptake of 125I-VLDL could be inhibited by unlabeled normal VLDL, although hyperlipemic VLDL was more effective. HDL did not compete to a significant extent. Heparin released lipoprotein lipase-like activity from peritoneal macrophages. Addition of heparin with VLDL resulted in a greater, more rapid elevation in intracellular triglycerides, which was partially inhibited by albumin. Free fatty acid and Intralipid also produced triglyceride accumulation in macrophages. The data showed that all three of the mechanisms examined could contribute to the metabolism of VLDL by macrophages and cause the production of triglyceride-rich cells with a "foamy" appearance, although the evidence suggested that the action of lipoprotein lipase was probably the most important in this process.
Response of rhesus serum high density lipoproteins to cycles of diet-induced hypercholesterolemia.
Authors: Fless G M , Juhn D , Karlin J , Rubenstein A , Scanu A M
Published: June 2011

Two male rhesus monkeys underwent cyclical feeding of a hypercholesterolemic diet (2% cholesterol, 25% coconut oil) and a low-fat Purina monkey chow diet. During the latter diet, high density lipoprotein (HDL) exhibited two components with peak densities of d = 1.081 g/ml and 1.109 g/ml named HDLL and HDLH, respectively. During the initial hypercholesterolemic stage, except for apo A-II which remained unchanged, there was a transient rise in HDL (mainly HDLL) as well as in HDL cholesterol and apo A-I, all reaching maximal values after about 2 weeks from the onset of the diet. The two HDL species changed neither in size nor density as compared to their baseline counterparts, but had a comparatively higher content in cholesteryl ester and lesser amounts of triglycerides and phospholipids as compared to the normocholesterolemic animal. With the development of overt hypercholesterolemia (plasma cholesterol levels above 400 mg/dl), both HDL particles increased in density due to the loss of surface components (phospholipids and unesterified cholesterol) and core triglycerides with only minor changes in protein and cholesteryl ester contents. At this stage, the same two animals exhibited significant changes in the size and buoyant density of LDL. When returned to a normal Purina chow diet, the animals' serum cholesterol levels declined rapidly to normal levels; normalization of the HDL distribution also occurred but at a comparatively later time (26 weeks). Our studies indicate that the two HDL subsets characteristic of the normocholesterolemic rhesus monkey undergo significant changes in buoyant density as a function of the stage of hypercholesterolemia and that changes in concentration and size mainly affect the HDLL subspecies. At levels of plasma cholesterol below 400 mg/dl, this cholesterol increment is reflected by a significant increase in the number of the HDL subspecies without the overt participation of the low density lipoprotein classes characteristic of the advanced hyperlipidemic stage. Since we previously reported that greatly increased levels of cholesteryl esters enriched low density lipoproteins, beta-VLDL (very low density lipoprotein) and pre-beta-VLDL during overt diet-induced hypercholesterolemia, it is apparent that cholesterol is distributed differently among lipoprotein particles containing either apo A-I, apo B, or apo E depending on its concentration in plasma.
Measurement in vivo of irreversible degradation of low density lipoprotein in the rabbit aorta. Predominance of intimal degradation.
Authors: Carew T E , Pittman R C , Marchand E R , Steinberg D
Published: June 2011

The development of a highly sensitive method for assessing, tissue by tissue, the rates of irreversible protein degradation in vivo has allowed us to quantify low density lipoprotein degradation in the normal rabbit aorta and to localize it. The method depends upon the fact that tyramine-cellobiose, like sucrose used in previous studies, can be covalently attached to proteins, enter cells with them, and then remains trapped within the cell after the remainder of the protein molecule has been degraded. Rabbit LDL (d = 1.02 to d = 1.06 g/ml) was labeled with 125I-tyramine-cellobiose and injected into rabbits. Aortic 125I content 24 hours later served as a cumulative measure of degraded LDL (after appropriate corrections for any intact, nondegraded LDL present). Calculated aortic degradation of LDL averaged 9.4 X 10(-3) percent of the plasma pool per g aortic wet weight per day (n = 6). Intimal cells, obtained by gentle swabbing, accounted for fully 40% of total aortic degradation even though the intima represented less than 5% of the aortic mass. Autoradiography confirmed the high concentration of label in the intima. Degradation of unmodified and reductively methylated LDL were compared. The fractional rate of degradation of methylated LDL by the intima was 50% to 60% of that for native LDL, indicating that 40% to 50% of LDL degradation in the intima, predominantly endothelial cells, is mediated by LDL receptors.
Endothelial transport of anionized and cationized ferritin in the rabbit thoracic aorta and vasa vasorum.
Authors: Baldwin A L , Chien S
Published: June 2011

Transport of anionized ferritins (AF,pl = 3.8-4.2), weakly cationized ferritins (WCF, pI = 7.8-8.1) and cationized ferritins (CF, pI greater than 9.0) was investigated in the rabbit aorta and vasa vasorum. After a 2-minute in situ perfusion, all ferritin species entered luminal vesicles and bound to the luminal endothelial membrane with a high surface density at vesicle necks and regions of cell overlap. In comparison to the aorta, the vasa vasorum had a higher surface density for AF, lower surface densities for CF and WCF, and fewer vesicles containing CF, WCF, or AF. In both types of vessels, vesicle loading of all ferritin species did not agree with a Poisson distribution. After perfusion times of up to 30 minutes, no abluminal vesicles or vasa vasorum endothelium contained CF or WCF; a few abluminal vesicles near cell borders contained AF. In the vasa vasorum, CF and AF entered the subendothelium via occasional fenestrae; AF, but not CF, also permeated the adventitia. Our findings indicate that: 1) binding sites for oppositely charged particles coexist in the same microdomains; 2) the glycocalyces of the vasa vasorum and aorta differ in their relative affinities for oppositely charged particles; 3) vesicular labeling with ferritin is not solely diffusive; and 4) vesicles do not traverse the aortic endothelium under these experimental conditions.
Effect of aspirin and salicylate on platelet-vessel wall interactions in rabbits.
Authors: Buchanan M R , Hirsh J
Published: June 2011

We performed studies to examine the mechanism responsible for the antithrombogenic effect of aspirin in experimental animals. We measured the effect of 10 and 100 mg/kg doses of aspirin, salicylate, or a combination of both on the accumulation of radiolabeled platelets onto injured carotid arteries in rabbits. The effects of these agents on thrombogenicity measured as platelet accumulation onto injured carotid arteries, were correlated with the ability to inhibit platelet thromboxane A2 and vessel wall prostacyclin synthesis. We found that a low dose of aspirin significantly inhibited platelet accumulation onto the injured vessels, while a high dose reversed this effect. Thromboxane A2 and prostacyclin production, however, were maximally inhibited in rabbits given either aspirin dose. The reversal of the antithrombotic effect of the low dose of aspirin by a high dose of aspirin was simulated by administering a combination dose of high-dose salicylate and low-dose aspirin. We concluded that the reversal of the antithrombotic effect of a 10 mg/kg dose of aspirin by a higher dose of aspirin could not be explained solely by the inhibition of PGI2 synthesis and was affected by the salicylate moiety of aspirin.
In vitro and in vivo interactions of Triton 1339 with plasma lipoproteins of normolipidemic rhesus monkeys. Preferential effects on high density lipoproteins.
Authors: Yamamoto K , Shen B , Zarins C , Scanu A M
Published: June 2011

Triton WR-1339 was incubated in vitro in various proportions with plasma from normolipidemic rhesus monkeys or with ultracentrifugally purified lipoproteins, and the products were examined by isopycnic density gradient ultracentrifugation, agarose column chromatography, electrophoretic and immunochemical techniques, and electron microscopy. Some experiments used apo A-I, apo A-II, or Triton labeled with either 125I or 131I. At concentrations of less than 10 mg/ml plasma, Triton interacted preferentially with HDL, changing lipoprotein size and density; Triton was progressively incorporated into the HDL particles, displacing apo E, apo A-I, and apo A-II. At concentrations above 10 mg/ml plasma, Triton displaced all apo A-I from the particle, and much lipid was dissolved into the Triton micelles. When Triton-treated HDL particles were used as a substrate for the enzyme LCAT, enzyme activity decreased in parallel to the displacement of apo A-I. There was no displacement of apo B from LDL nor any loss of lipids; but the particles became deformed and formed rouleaux. A single intravenous dose of Triton WR-1339 administered to a normolipidemic monkey (N) and to a hypercholesterolemic monkey (H) resulted in concentration-dependent HDL changes similar to those observed in vitro. LDL was less affected by Triton, with changes occurring only at high doses. After these structural changes, intravenously injected 131I apo A-I disappeared rapidly from the circulation; 125I apo A-II disappeared less rapidly. These increased clearances were accompanied by a drop in apo A-I plasma levels and the disappearance of HDL particles from plasma. The lipoprotein and apolipoprotein patterns returned to normal 14 days after Triton. We conclude that Triton WR-1339, when exposed to rhesus plasma in vitro or in vivo, interacts preferentially with HDL in a dose-dependent manner. At low concentrations, Triton acts on surface components of the HDL particle; at higher concentrations, Triton penetrates the particle, causing structural disruption. Because of its high affinity for HDL, Triton WR-1339 is a useful reagent for study of HDL structure-function relationships.
Verapamil enhances receptor-mediated endocytosis of low density lipoproteins by aortic cells in culture.
Authors: Stein O , Leitersdorf E , Stein Y
Published: June 2011

Bovine aortic endothelial and smooth muscle cells (SMC) and human skin fibroblasts (HSF) were used to study the effect of verapamil on cellular interactions with human low density lipoprotein (LDL). Verapamil, 10 to 50 microM, increased 125I-LDL uptake and degradation by 70% to 200% in the various cells after 24 to 48 hours of incubation. The increase in the total amount of LDL endocytosed, labeled with 3H-cholesteryl linoleate (3H-CL), was comparable to that determined with 125I-LDL. In HSF and SMC, a delay in 125I-LDL degradation and hydrolysis of 3H-CL was seen in cells treated for 3 to 24 hours with verapamil. Pretreatment of HSF with 50 microM verapamil for 24 hours and incubation with 2 to 50 micrograms 125I-LDL protein/ml for 1 hour resulted in a 50% to 200% increase in heparin releasable and in a 40% to 130% increase in cellular 125I-LDL. Thus, the increase in 125I-LDL binding and uptake in verapamil-treated cells was apparently due to an increase in receptor number, rather than in receptor affinity. The effect of verapamil on LDL uptake and degradation was also seen in cells that were pretreated for 24 hours and incubated with 125I-LDL in the absence of verapamil. The effect of verapamil was not apparent in LDL receptor-negative cells. Cycloheximide blocked the verapamil effect. The Na+ channel blocker, tetrodotoxin x 10(-6) M, caused a 30% to 50% increase in the total amount of LDL endocytosed, but no delay in LDL degradation; amiloride 2 x 10(-3) M was not effective. If the presently described effect of verapamil also occurs in vivo, this might contribute to the reported beneficial effects of Ca++ channel blockers in experimental atherosclerosis by promoting transfer of LDL cholesteryl ester from the aortic interstitium to a catabolic compartment.
Role of the low density lipoprotein receptor in penetration of low density lipoprotein into rabbit aortic wall.
Authors: Wiklund O , Carew T E , Steinberg D
Published: June 2011

The present study was designed to determine whether binding of low density lipoprotein (LDL) to endothelial LDL receptors contributes significantly to the penetration of LDL into the normal rabbit aorta. Initial flux rate was used as a measure of uptake of LDL. Reductive methylation of LDL is known to block its recognition by the LDL receptor. Therefore, the difference in flux rates of native LDL and reductively methylated LDL (methyl-LDL) was assumed to represent the receptor-dependent uptake. Native LDL and methyl-LDL were labeled with different isotopes (125I or 131I) and both were injected simultaneously into the same rabbit. After 30 to 60 minutes, trichloroacetic acid-precipitable counts were determined in aortic specimens. The initial flux rates, expressed as plasma clearance (nl/g/hr), were 1787 for native LDL and 1924 for methyl-LDL. The difference was not significant, which suggests that the flux of LDL into the aorta is not significantly dependent upon, or regulated by, endothelial LDL receptors, but is mediated by other mechanisms.
Structural and hemodynamic response of peripheral arteries of macaque monkeys to atherogenic diet.
Authors: Armstrong M L , Heistad D D , Marcus M L , Megan M B , Piegors D J
Published: June 2011

The arteries of monkeys given atherogenic diets develop marked intimal thickening and medial thinning, but luminal size apparently changes minimally. The hemodynamic significance of the atherosclerotic changes is therefore uncertain. To evaluate vascular function in atherosclerotic arteries, we studied the hind-limb vessels of adult male rhesus and cynomolgus monkeys to assess the structural and hemodynamic responses to an atherogenic diet given for about 1.5 years or for much longer periods (6.5 years for rhesus and 4.3 years for cynomolgus monkeys). The intimal cross-sectional area greatly increased after the atherogenic diet, but there was no significant luminal narrowing after either the 1.5-year diet or the longer diet periods. The media of atherosclerotic arteries showed focal atrophy and focal thinning after pressure fixation, but the total medial mass was not decreased even after the long diet periods. Hemodynamic studies indicated mild functional impairment in the atherosclerotic vessels; resting resistance increased and vasodilator responses decreased, but adrenergic responses were preserved. Thus, the marked changes that occur in the arterial wall in experimental primate atherosclerosis include adaptations to lesion formation that permit a long prestenotic phase of atherosclerosis in which vascular dysfunction is minimal.
Platelet and megakaryocyte changes in cholesterol-induced experimental atherosclerosis.
Authors: Martin J F , Slater D N , Kishk Y T , Trowbridge E A
Published: June 2011

Rabbits were fed either 2 g cholesterol in 10 ml olive oil daily with normal diet (n = 5) or normal diet alone (n = 5). After 12 weeks, the cholesterol-fed animals had developed fatty plaques involving 24% +/- 4% of the surface area of the aorta; the control animals had none. Mean platelet volume was significantly smaller (p less than 0.04) in the cholesterol-fed animals (4.1 +/- 0.3 fl) compared with the controls (4.8 +/- 0.4 fl). The heterogeneity of the average volume distributions of the two groups, characterized by the statistical parameters of the coefficient of variation, skewness, and kurtosis, was also significantly different. Platelet count was significantly higher (p less than 0.001) in the cholesterol-fed group (7.48 +/- 1.06 x 10(11) platelets/liter blood) compared to the control group (4.86 +/- 0.60 x 10(11) platelets/liter blood). Mean megakaryocyte cytoplasmic volume was significantly larger (p less than 0.001) in the cholesterol-fed rabbits (12,262 +/- 1485 fl) compared with controls (6,814 +/- 761 fl). The range of cytoplasmic volumes was also significantly increased in the cholesterol-fed rabbits. A significant (p less than 0.01) increase in mean megakaryocyte nuclear volume in the cholesterol-fed animals was accompanied by a nonsignificant increase in mean nuclear DNA content: 30.2 +/- 3.7 N compared with a control value of 23.6 +/- 4.0 N. This evidence indicates that a high cholesterol diet in rabbits is associated with changes in platelet production from megakaryocytes as well with as the development of atherosclerosis.
Behavioral antecedents of coronary heart disease and atherosclerosis.
Authors: Manuck S B , Kaplan J R , Matthews K A
Published: June 2011

Over 50 epidemiologic, clinical, and experimental studies of behavioral influences on atherosclerosis and CHD have been reviewed; of these investigations, no more than five were published prior to 1975. Despite some inconsistencies and occasional conceptual and methodologic problems in the studies comprising this relatively young literature, the preponderance of available evidence indicates that psychosocial variables play a significant role in coronary disease. To summarize briefly, the Type A behavior pattern has been found predictive of new CHD in nearly all prospective studies of initially healthy individuals, and therapeutic modification of Type A has been shown to reduce risk of recurrent nonfatal MI. Among most prospective studies of post-MI patients and of persons at heightened risk for CHD due to elevations in traditional risk factors, however, Type A has not been found to predict, respectively, recurrence of MI or initial clinical events. Additionally, Type A individuals have shown more extensive coronary artery atherosclerosis on angiographic examination than Type Bs in a minority of studies, and, generally, only where Type A behavior has been measured by the SI. It is noted that many of these clinical studies may be faulted, though, for their use of small and heterogeneous patient samples and for possible biases in the selection and recruitment of subjects. In contrast to the globally defined Type A pattern, a high potential for hostility and an inability or unwillingness to express anger (anger-in) have emerged as significant predictors or correlates of coronary disease in all epidemiologic and clinical studies in which these variables have been examined. These consistent results suggest that a predisposition to hostility and anger, and the inhibited expression of such feelings, represent a "toxic" component of the Type A pattern. Several recent prospective investigations indicate also that high levels of life stress and possession of poor or inadequate social resources are predictive of CHD. The concepts of life stress, social network, and social support, as well as relationships among these variables, are not well-understood, however, and much additional work is needed to identify specific pathogenic and protective attributes of the social environment. In addition to studies of the psychosocial antecedents of CHD in human beings, there now are several published studies of behavioral influences on the development of coronary lesions in animal models.(ABSTRACT TRUNCATED AT 400 WORDS)
Monocyte chemotactic factor produced by large vessel endothelial cells in vitro.
Authors: Berliner J A , Territo M , Almada L , Carter A , Shafonsky E , Fogelman A M
Published: June 2011

Cultured rabbit aortic and human carotid artery endothelial cells produced a factor that was chemotactic for monocytes but not for neutrophils. Checkerboard analysis showed that the activity was due to chemotaxis and not to chemokinesis. The factor was produced in both serum-containing and serumless media. Treatment with carboxypeptidase and trypsin resulted in inhibition of chemotactic activity, indicating that the factor is a peptide. Medium from cultures of rabbit aortic, human carotid artery, and human umbilical vein endothelial cells previously exposed to beta migrating very low density lipoprotein (beta-VLDL) had substantially more chemotactic activity than medium from untreated cells or cells exposed to low density lipoprotein. beta-VLDL alone had no chemotactic activity. We conclude that large vessel endothelial cells produce a monocyte chemotactic factor that is increased after exposure of the cells to beta-VLDL.
Observations on leukocytes from patients with severe familial hypercholesterolemia.
Authors: Dresel H A , Via D P , Stöhr M , Elchner U , Gnasso A , Postiglione A , Blin N , Augustin J , Schettler G
Published: June 2011

Differences in light scatter and fluorescence emission of blood leukocytes from patients with familial hypercholesterolemia (FH) and normal patients incubated with oil red O and r(NBD-Cl)-acetyl-LDL were observed by flow-through cytofluorometry and used to distinguish a subclass of leukocytes. The appearance of this subpopulation of leukocytes in FH apparently correlated with the excessive hypercholesterolemia. In addition, microscopic evaluation of blood smears suggested the formation of small cytoplasmic vacuoles in a population of FH monocytic cells. While these are preliminary observations on a small number of patients, they warrant further study. However, the use of lipophilic dyes and fluorescent acetyl-LDL in combination with flow cytometry may be another useful means for evaluation of FH.
Vascular injury: quantification of experimental focal endothelial denudation in rats using indium-111-labeled platelets.
Authors: Reidy M A , Yoshida K , Harker L A , Schwartz S M
Published: June 2011

Rat platelets were labeled with indium-111 (111In) and injected into rats whose aortas were subjected to endothelial denudation. A plot of 111In activity vs the number of missing endothelial cells showed a direct correlation between these parameters and it was possible to detect endothelial denudation when approximately 600 cells were removed. These studies also revealed that intact adjacent endothelium from aortas subjected to injury had detectably increased 111In activity compared with endothelium of control, uninjured rats. This activity was not found if 111In-platelets were preincubated with acetylsalicylic acid (1.3 mM) prior to injection and subsequent denudation procedure. To test if 111In platelet activity could be transported to sites distant from the site of injury, a small catheter (PE 50) was passed down the carotid artery so that it reached the aortic arch or inserted via a femoral artery to the iliac-aortic bifurcation. Significant increases in 111In activity were detected in the lower thoracic aorta when the catheter was introduced into the aortic arch but not when the catheter was introduced via the femoral artery. Morphologic evaluation of these sites showed no endothelial cell loss or adhering platelets. These studies suggest that detectable uptake of released platelet products may occur at distal sites of intact endothelium.
Neutrophil oxidants inactivate alpha-1-protease inhibitor and promote PMN-mediated detachment of cultured endothelium. Protection by free methionine.
Authors: Stroncek D F , Vercellotti G M , Huh P W , Jacob H S
Published: June 2011

Activated granulocytes have been implicated in mediating pulmonary endothelial damage in the Adult Respiratory Distress Syndrome. In another lung disease, emphysema, pulmonary granulocytes (PMNs) are thought to be doubly responsible for lung dissolution: they release potent proteolytic enzymes including elastase, and they generate reactive oxygen species that oxidize a reactive site methionine group in alpha-1-protease inhibitor (alpha-1-PI) rendering it, in turn, impotent as an anti-elastase. This suggested an analogous scenario for pulmonary vascular damage: namely, undefended PMN elastase might also mediate endothelial injury. Our strategy to prove this notion used 51chromium-labeled human endothelial cells exposed to intact PMN or to enucleate "neutroplasts." The latter are elastase-free cytoplasmic blebs derived from PMN. When activated, both PMN and neutroplasts generate similar amounts of toxic oxygen species; yet neutroplasts caused insignificant endothelial damage, measured as 51Cr "lift-off"from anchoring matrix (PMN = 24.3% +/- 1.8% vs neutroplast = 1.2% +/- 0.4%; p less than 0.001). Adding pure elastase back to neutroplasts increased endothelial cell lift-off (7% +/- 0.2%). Although the prototypic serine protease inhibitor phenyl methylsulfonylfluoride (PMSF) protected endothelium from PMNs, pure alpha-1-PI (also a potent anti-elastase) when added in physiologic amounts did not protect endothelial cells from PMN assault, suggesting that PMN oxidants might inactivate it. By adding exogenous myeloperoxidase (MPO) to MPO-deficient neutroplasts, we demonstrated that MPO-dependent oxidants, probably N-chloramines, are critical inactivators of alpha-1-PI. This was further confirmed since added free methionine, a scavenger of chloramine, protected alpha-1-PI from inactivation by reagent chloramine or that produced by rearmed neutroplasts or PMN.(ABSTRACT TRUNCATED AT 250 WORDS)
Ag(c): recognition by a monoclonal antibody.
Authors: Robinson M T , Schumaker V N , Butler R , Berg K , Curtiss L K
Published: June 2011

A monoclonal antibody directed against human apolipoprotein B, which was previously shown in family studies to detect allelic variations (J Biol Chem 1984; 259:6423-6430), has now been identified with the Ag(c) factor. This identification allows the location of the Ag system on the structural gene for apolipoprotein B and on the short arm of human chromosome 2. The epitope corresponding to Ag(c) is located within the amino acid sequence common to apolipoproteins B-100 and B-48. Since a single molecule of apolipoprotein B-100 is present on human LDL, individual LDL possesses either the epitope corresponding to Ag(c) or that corresponding to Ag(g). These studies on allelic variation among human apolipoprotein B species parallel similar studies in animals in which a relationship to atherosclerosis was found.
A proposed structure of chondroitin 6-sulfate proteoglycan of human normal and adjacent atherosclerotic plaque.
Authors: Wagner W D , Salisbury G J , Rowe H A
Published: June 2011

Chondroitin sulfate proteoglycan monomers were prepared from intima media minces of grossly normal human aorta and adjacent fatty fibrous atherosclerotic plaques. Glycosaminoglycan chains prepared from monomer from normal aorta displayed a normal distribution profile on Ultrogel ACA 54 with a Kav of 0.48, whereas those of atherosclerotic aorta displayed a bimodal distribution (major peak, Kav 0.35; minor peak, Kav 0.70). The Mr of glycosaminoglycans from normal aorta was estimated to be 1.5 X 10(4). For atherosclerotic aorta, the majority of chains were 2.0 X 10(4) while the smaller population was 1.2 X 10(4). All glycosaminoglycans were identified as chondroitin sulfate sulfated at the C-6 position. The amino acid compositions of both core proteins were similar with Mr of about 1.6 X 10(5). After beta-elimination in the presence of sodium borohydride prior to acid hydrolysis, chondroitin sulfate proteoglycan from normal aorta had reductions in serine from 109 to 68 and in threonine from 117 to 55. For the monomer from atherosclerotic plaque, reductions in serine and threonine, respectively, were from 103 to 81 and from 107 to 77 residues per 1000. The results suggested fewer chondroitin sulfate chains and oligosaccharides on the core protein in the proteoglycan of atherosclerotic plaque. Compared to normal aorta, substituted serines and threonines in the proteoglycan of atherosclerotic plaque were about half, respectively, 38% vs 21% for serine, 53% vs 28% for threonine. It is estimated that in atherosclerotic plaque there are fewer, but longer, chondroitin sulfate chains per core protein, translating into a smaller overall monomer size in atherosclerotic plaque.
Sex hormone levels in young Indian patients with myocardial infarction.
Authors: Sewdarsen M , Jialal I , Vythilingum S , Desai R
Published: June 2011

The finding of abnormal levels of sex hormones in men with coronary artery disease has led to the hypothesis that alterations in sex hormones may represent an important risk factor for myocardial infarction. In this study, the sex hormone profile of 28 young men (aged less than 40 years) with myocardial infarction was compared with 28 age- and weight-matched normal men. Although the mean total serum estradiol levels and the free estradiol index of the patients and controls were similar, the mean serum total testosterone level and the free testosterone index were significantly lowered in the patients with myocardial infarction (p less than 0.01). The ratio of serum estradiol to testosterone was significantly increased in the patients (p = 0.0005) and correlated with serum cholesterol, triglycerides, and plasma glucose. A significant inverse correlation was also demonstrated between total testosterone and serum cholesterol and triglycerides. Hence, the results of this study support the hypothesis that low plasma testosterone and an increased estradiol-to-testosterone ratio may be important risk factors for myocardial infarction.
Estradiol-17 beta affects estrogen receptor distribution and elevates progesterone receptor content in baboon aorta.
Authors: Lin A L , Gonzalez R , Carey K D , Shain S A
Published: June 2011

We used the synthetic estrogen R2858 (moxestrol) and estradiol-17 beta, respectively, to characterize the estrogen receptor in baboon (Papio sp.) aortic or myocardial cytoplasmic and nuclear preparations. We observed regional differences in the cytoplasmic fraction estrogen and progesterone receptor content of aortic arch, thoracic aorta, and abdominal aorta when tissues from either oophorectomized or oophorectomized estradiol-17 beta-treated subjects were compared. The estrogen receptor content was highest in the abdominal aorta and lowest in the aortic arch. In contrast, the cytoplasmic fraction progesterone receptor content was highest in the aortic arch and lowest in the abdominal aorta. The nuclear fraction estrogen receptor could not be demonstrated in preparations from cardiovasculature of oophorectomized female baboons. The use of Silastic implants to administer a physiologic concentration of estradiol-17 beta to oophorectomized female baboons caused a 20% to 50% reduction in cytoplasmic fraction estrogen receptor content, which was quantitatively accounted for by the appearance of estrogen receptor in the corresponding nuclear aortic or myocardial preparation. Estrogen administration caused a 20% to 40% increase in cytoplasmic fraction progesterone receptor content in both myocardium and aorta; however, differences were significant only for abdominal aorta (p less than 0.05). Estradiol-17 beta treatment caused a tenfold increase in uterine cytoplasmic fraction progesterone receptor content in treated as compared to oophorectomized control females, suggesting that baboon cardiovasculature is less sensitive to changes in endogenous estrogen concentration than is uterus. The ability of estradiol-17 beta to affect apparent intracellular distribution of baboon cardiovascular estrogen receptors and to elevate cytoplasmic fraction progesterone receptor content suggests that these estrogen receptors are physiologically functional and indicates that estrogen may directly regulate primate cardiovascular cell function.
Relationship of plasma lipoproteins and the monocyte-macrophage system to atherosclerosis severity in cholesterol-fed pigeons.
Authors: St Clair R W , Randolph R K , Jokinen M P , Clarkson T B , Barakat H A
Published: June 2011

The purpose of this study was to determine if there was a relationship between plasma beta-VLDL concentrations and atherosclerosis severity in cholesterol-fed pigeons, and if so, whether this correlated with cholesterol accumulation in tissues rich in cells of the monocyte-macrophage system (liver, spleen, peritoneal macrophages). Among individual birds consuming a cholesterol-containing diet, plasma beta-VLDL concentrations ranged from 14 to 1979 mg/dl. In these animals the cholesterol content of peritoneal macrophages, liver, and spleen was positively correlated with plasma concentrations of beta-VLDL and LDL, but not with HDL. When added in vitro to peritoneal macrophages from control pigeons, beta-VLDL stimulated a nearly 200-fold increase in cholesterol accumulation, but there was no relationship between the ability of beta-VLDL to stimulate macrophage cholesterol accumulation and the extent of atherosclerosis in the animal from which the beta-VLDL was obtained. Cholesterol feeding for up to 6 months increased the severity of atherosclerosis in both atherosclerosis-susceptible White Carneau and resistant Show Racer pigeons, but there was no correlation of atherosclerosis severity with beta-VLDL or HDL concentrations, and only a weak relationship with LDL concentrations. The results are consistent with the conclusion that atherosclerosis susceptibility in pigeons cannot be explained by quantitative or qualitative differences in plasma beta-VLDL. Instead, differences in susceptibility are probably mediated at the level of the arterial wall, perhaps by genetic differences that influence the way an individual animals' arterial cells (endothelial, smooth muscle, macrophages) interact with specific plasma lipoproteins.
Lipid and lipoprotein abnormalities associated with coronary heart disease in patients with insulin-dependent diabetes mellitus.
Authors: Laakso M , Pyörälä K , Sarlund H , Voutilainen E
Published: June 2011

We measured serum lipid and lipoprotein levels in 63 insulin-dependent diabetic (IDD) patients (32 men, 31 women) and in 63 nondiabetic control subjects (32 men, 31 women) without coronary heart disease (CHD) and in 19 IDD patients (11 men, 8 women) and in 18 nondiabetic subjects (8 men, 10 women) with CHD. All diabetic patients had postglucagon C-peptide levels of less than 0.60 mmol/liter and none had signs of renal failure. Male IDD patients with CHD had higher levels of total cholesterol, low density lipoprotein (LDL) cholesterol, total triglycerides, very low density lipoprotein (VLDL) triglycerides and lower level of high density lipoprotein (HDL) cholesterol than male IDD patients without CHD. In female IDD patients, similar lipid and lipoprotein abnormalities were observed between the groups of diabetics with and without CHD except for total cholesterol, which was the same in both groups. A comparison between IDD patients without CHD and nondiabetic control subjects without CHD showed no difference in lipid and lipoprotein levels in males; female IDD patients without CHD showed even higher levels of HDL and HDL2 cholesterol and lower levels of VLDL triglycerides than nondiabetic controls. Our results indicate that in IDD patients without nephropathy and CHD, the lipid and lipoprotein levels do not differ from nondiabetic controls, but in IDD patients with CHD the lipid and lipoprotein pattern is similar to that known to be characteristic for nondiabetic patients with CHD.
Superoxide initiates oxidation of low density lipoprotein by human monocytes.
Authors: Hiramatsu K , Rosen H , Heinecke J W , Wolfbauer G , Chait A
Published: June 2011

Human mononuclear cells were used to evaluate the role of superoxide in the oxidation of low density lipoprotein (LDL). Unstimulated cells produced little superoxide or LDL oxidation as assayed by lipid peroxide content. Stimulation of the cells with phorbol myristate acetate (PMA) resulted in an increase both in superoxide production and in LDL oxidation. Mononuclear cell-mediated LDL oxidation was time- and cell number-dependent and was markedly enhanced by the presence of Fe (10 microM). Superoxide was required for the initiation of LDL oxidation as indicated by inhibition of the reaction by early addition of superoxide dismutase (SOD). Propagation of LDL oxidation was superoxide-independent, since the later addition of SOD resulted in progressively less inhibition of LDL oxidation. Propagation of LDL oxidation also was, in part, cell-independent as indicated by continued oxidation of LDL when mononuclear cells were removed following a 1 to 8 hour period with cells. Optimal LDL oxidation required the presence of mononuclear cells throughout the incubation period, suggesting that cellular factors in addition to superoxide play a role in LDL oxidation. Further evidence for the role of superoxide in the oxidation of LDL by mononuclear cells was obtained with cells from patients with genetic deficiencies of either superoxide generation (chronic granulomatous disease) or myeloperoxidase. PMA-stimulated cells from a patient with chronic granulomatous disease neither generated superoxide nor modified LDL. Incubation of LDL with cells from a patient with myeloperoxidase deficiency (in which superoxide production is normal or increased) resulted in oxidation of the lipoprotein equivalent to that observed with normal cells. Other inhibitors of oxidation reactions also were tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoprotein B allotypes MB19(1) and MB19(2) in subjects with coronary artery disease and hypercholesterolemia.
Authors: Young S G , Bertics S J , Scott T M , Dubois B W , Beltz W F , Curtiss L K , Witztum J L
Published: June 2011

We recently characterized a common form of genetic polymorphism in human apolipoprotein (apo) B, using the specific monoclonal antibody MB19 (Young SG, et al. Proc Natl Acad Sci USA 1986; 83:1101-1105). Antibody MB19 binds apo B with one of three distinct patterns of immunoreactivity (strong, intermediate, or weak). These three binding patterns are the result of the codominant inheritance of two common apo B alleles which encode for apo B allotypes MB19(1) and MB19(2), which have high and low affinity, respectively, for antibody MB19. Thus, subjects with strong or weak binding patterns are homozygous for MB19(1) or MB19(2), respectively, whereas those with an intermediate pattern are heterozygotes. To assess whether the MB19 polymorphism was related to hypercholesterolemia (HC) or to coronary artery disease (CAD), we determined the MB19 binding pattern and plasma lipoprotein concentrations in 129 normal subjects, 51 patients with HC, and 149 patients with CAD. The percentages of normal subjects having the strong, intermediate, and weak binding patterns were 11.6%, 41.9%, and 46.5%, respectively. The frequency of the three MB19 binding patterns was nearly the same in the groups with HC and CAD. Also, within each of the three groups of subjects, the MB19 binding pattern did not influence the plasma lipoprotein concentrations. We conclude that the genetic polymorphism in apo B defined by antibody MB19 is a common allelic variation in apo B, and that in the populations studied, it does not appear to be associated with the development of coronary artery disease or hypercholesterolemia.
Effect of nicardipine and verapamil on in vitro albumin transport in rabbit thoracic aorta.
Authors: Tedgui A , Chiron B , Curmi P , Juan L
Published: June 2011

Calcium antagonists have been shown to have an antiatherogenic effect. We investigated the effect of nicardipine and verapamil on the albumin transport across the media of excised rabbit thoracic aorta. The effect of nicardipine was also tested in deendothelialized arteries. The vessels were incubated for 90 minutes in oxygenated Krebs or 80 mM KCl solutions at in vivo length and at a transmural pressure of 70 mm Hg. The transmural concentration profiles of 125I-albumin across the media were measured by a frozen serial sectioning technique. In deendothelialized arteries, K+ decreased the mean medial uptake of labeled albumin, whereas 10(-7) M nicardipine in Krebs increased the uptake and 10(-9) M nicardipine had no effect. In a K+-rich solution, containing 10(-7) or 10(-9) M nicardipine, the medial uptake was lower than, but not significantly different from, that in Krebs. In intact K+-treated vessels, the wall concentrations near the lumen were increased and concentration gradients across the media were observed, possibly due to an increase in endothelial permeability following K+-induced contraction of the endothelial cells. This effect was reversed by the addition of 10(-7) M nicardipine, but not by 10(-7) M verapamil. Nicardipine and verapamil (10(-7) M) in Krebs solution enhanced the albumin uptake by the media of intact arteries. This effect on the permeability of the media may be related to the antiatherogenic effect of calcium antagonists.
Body mass, blood pressure, glucose, and lipids. Does plasma insulin explain their relationships?
Authors: Cambien F , Warnet J M , Eschwege E , Jacqueson A , Richard J L , Rosselin G
Published: June 2011

Obesity, hypertension, a high plasma level of glucose, and some lipid abnormalities (high plasma levels of cholesterol and triglycerides) often occur in the same individuals. Some authors have postulated that the elevated levels of plasma insulin in obese individuals may explain this association. To explore this hypothesis further, the relationships between body mass index, fasting plasma glucose and insulin, blood pressure, serum lipids, and apoproteins were investigated in a group of 2144 healthy middle-aged men. Analysis of the data show that the associations between body mass index and blood pressure or lipid variables are largely independent of plasma glucose and insulin. Plasma glucose is strongly related to blood pressure in nonobese subjects. Plasma insulin is not associated with blood pressure independently of body mass index and plasma glucose; however, the simultaneous elevation of body mass index, plasma glucose, and insulin is strongly associated with blood pressure. The results also confirm that plasma insulin is positively related to triglycerides and negatively related to high density lipoprotein cholesterol independently of plasma glucose and body mass index.
Plasma exchange and low density lipoprotein apheresis in Watanabe heritable hyperlipidemic rabbits.
Authors: Kano M , Koizumi J , Jadhav A , Thompson G R
Published: June 2011

Comparison of the effects of plasma exchange using lipoprotein-deficient plasma with those of LDL apheresis using a dextran sulphate column was undertaken in two groups of Watanabe heritable hyperlipidemic rabbits pre-labelled with 3H-cholesterol. Total and HDL cholesterol were reduced more by plasma exchange but HDL cholesterol rebounded higher after LDL apheresis; rises in HDL cholesterol correlated with preceding decreases in both HDL and total cholesterol. An increase in the specific activity of HDL cholesterol occurred on the day after each procedure, being more marked after plasma exchange, and was accompanied by a decrease in the cholesterol/phospholipid ratio of HDL. These results suggest that an influx of extravascular HDL into plasma occurred after both procedures, resulting in mobilization of tissue cholesterol.
Aspirin treatment reduces platelet resistance to deformation.
Authors: Burris S M , Smith C M , Rao G H , White J G
Published: June 2011

The present investigation has evaluated the influence of aspirin, its constituents, and other nonsteroidal anti-inflammatory agents on the resistance of human platelets to aspiration into micropipettes. Aspirin increased the length of platelet extensions into the micropipette over the entire negative tension range of 0.04 to 0.40 dynes/cm after exposure to the drug in vitro or after ingestion of the agent. Other cyclooxygenase inhibitors, ibuprofen and indomethacin, did not increase platelet deformability. The influence of aspirin was mimicked to some degree by high concentrations of salicylic acid, but acetylation of platelets with acetic anhydride had little influence on platelet deformability. Incubation of platelets with both salicylic acid and acetic anhydride had no more effect than salicylic acid alone. Benzoic acid, chemically similar to salicylic acid, had a minimal effect. The studies demonstrate that aspirin makes platelets more deformable, while components of the drug or other nonsteroidal antiinflammatory agents and cyclooxygenase inhibitors do not have the same influence on resistance to deformation.
Unsaturated fatty acids enhance low density lipoprotein uptake and degradation by peripheral blood mononuclear cells.
Authors: Loscalzo J , Freedman J , Rudd M A , Barsky-Vasserman I , Vaughan D E
Published: June 2011

The precise mechanism by which unsaturated fatty acids lower low density lipoprotein cholesterol is not known. Because cis-unsaturated fatty acids incorporated in cell membranes increase membrane fluidity and can thereby dramatically alter membrane-dependent cellular functions, we examined the effect of linoleate and oleate incorporation in peripheral blood mononuclear cell membranes on the physical properties of the membrane and concomitantly on low density lipoprotein uptake and degradation. We found that membrane enrichment with linoleate increased the rate of low density lipoprotein degradation in both freshly isolated and derepressed mononuclear cells. Enrichment with oleate led to similar increases in degradation. "Specific" low density lipoprotein uptake by derepressed cells was also enhanced by linoleate and oleate incorporation. Enrichment with both of these fatty acids produced an increase in membrane fluidity, as indicated by a reduction in the steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene incorporated in the membrane. In contrast, stearate enrichment had little effect on uptake or degradation of low density lipoprotein, nor did it affect membrane fluidity. These data point to a novel mechanism for the reduction in low density lipoprotein produced by unsaturated fatty acids that involves their physical effects on cell membranes as it relates to metabolism of the lipoprotein.
Regulation of vascular smooth muscle cell growth by endothelial-synthesized extracellular matrices.
Authors: Herman I M , Castellot J J
Published: June 2011

Previous work has demonstrated that aortic endothelial cells (EC) produce a heparin-like inhibitor of smooth muscle cell (SMC) growth when both cell types were cultured on plastic. We have now tested the influence of the extracellular matrix on this EC-SMC interaction. Specifically, we examined: 1) the role of different substrates (plastic, fibronectin, monomeric, and fibrillar collagens I and III, and EC-derived matrices) on the growth rate and population density of SMC; 2) the heparin-sensitivity of SMC on these diverse substrates; and 3) the effect of these same substrates on EC ability to secrete heparin-like and polypeptide inhibitors of SMC growth. SMC demonstrated a sixfold difference in sensitivity to heparin when grown on different substrates, with the following rank order: EGTA matrix greater than collagens = plastic = fibronectin greater than deoxycholic acid (DOC) matrix. Maximally, we found a 10-fold difference in the potency of the inhibitory activity secreted by EC grown on different substrates, with the following order: plastic = EGTA matrix greater than fibronectin greater than collagens = DOC matrix. Treatment of the conditioned mediums with heparinase and trypsin indicated that 58% to 76% of the inhibitory activity was due to heparin-like species, and 24% to 42% was due to protein(s). When EC cultured on EGTA matrix are compared to those pleated on DOC matrix, the potency of the heparin-like and peptide inhibitory activities increased 8- and 17-fold, respectively. Hypothetically, one would predict a 60-fold change in the potency of the antiproliferative effect if the contributions of substrate to EC production of inhibitors and SMC sensitivity were additive.(ABSTRACT TRUNCATED AT 250 WORDS)