bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of plasma fibrinogen: relation to body weight, waist-to-hip ratio, smoking, alcohol, age, and sex. Results from the second MONICA Augsburg survey 1989-1990.
Authors: Krobot K , Hense H W , Cremer P , Eberle E , Keil U
Published: June 2011

In the second World Health Organization MONItoring Trends and Determinants in CArdiovascular Disease (MONICA) Augsburg survey in 1989-1990 (n = 4,940), the association between nephelometric plasma fibrinogen level and lifestyle-related potential determinants was assessed in 4,434 subjects aged 25-74 years (89.8% of participants). Irrespective of pregnancy and the use of oral contraceptives, crude fibrinogen values were consistently higher in women than in men of all ages (age-standardized difference, 12.2 mg/dl; 95% confidence interval, 7.0-17.4 mg/dl). Fibrinogen concentrations were positively correlated (p less than or equal to 0.0001) with age, body mass index, and waist-to-hip ratio in both sexes and with cigarette smoking in men and were negatively correlated with alcohol consumption in both sexes. In multiple linear regression analyses using categorized determinants as independent variables, a strongly J-shaped relation for body mass index in women and a linear association for waist-to-hip ratio in men were revealed. Smoking had a dose-dependent effect on fibrinogen concentration in men but a lesser effect in women. For alcohol consumption a U-shaped association was found, particularly in men. The curvilinear relations were confirmed in multiple polynomial regression models using continuous determinant variables. The potential epidemiological impact of a determinant was assessed by calculating differences in adjusted fibrinogen concentrations associated with the 10th and 90th percentile values of the determinant distributions actually observed among the study participants. This impact on the population fibrinogen level was most pronounced for age in both sexes, followed by body mass index, cigarette smoking, and alcohol consumption in women and by smoking, waist-to-hip ratio, and alcohol consumption in men.(ABSTRACT TRUNCATED AT 250 WORDS)
Superoxide-dependent stimulation of leukocyte adhesion by oxidatively modified LDL in vivo.
Authors: Lehr H A , Becker M , Marklund S L , Hübner C , Arfors K E , Kohlschütter A , Messmer K
Published: June 2011

Low density lipoprotein modified by oxidation (Ox-LDL) causes adhesion of leukocytes to the endothelium, a feature common in early atherogenesis. Because leukocyte adhesion under various pathophysiological conditions involves superoxide generation, we explored the possibility that superoxide is likewise involved in leukocyte adhesion in response to Ox-LDL. For our studies, we used the dorsal skin fold chamber model for intravital microscopic observation of leukocyte-endothelium interactions in hamsters. We show here that injection of human LDL (4 mg/kg LDL cholesterol oxidatively modified by incubation in 7.5 microM Cu2+ for 18 hours at 37 degrees C) elicited in control hamsters (n = 7) the rolling and adhesion of circulating leukocytes along the endothelium of arterioles and postcapillary venules. This adhesion was significantly attenuated when hamsters were pretreated with bovine copper-zinc-superoxide dismutase (CuZn-SOD, 0.25 mg/kg, n = 7) or heparin (2,000 IU/kg, n = 7). The CuZn-SOD infusion and the heparin-induced release of extracellular SOD from endothelial cell surfaces to plasma resulted in nearly equal plasma SOD activities. Further inhibition of Ox-LDL-induced leukocyte adhesion could not be achieved by increasing the dose of CuZn-SOD to 5 mg/kg (n = 6). Pretreatment of the hamsters with inactivated CuZn-SOD showed no effect. These results indicate that Ox-LDL stimulates leukocyte adhesion through a superoxide-dependent step, and they indicate a possible mechanism by which antioxidants might inhibit the onset of experimental and clinical atherosclerosis.
Probucol increases the selective uptake of HDL cholesterol esters by Hep G2 human hepatoma cells.
Authors: Pfeuffer M A , Richard B M , Pittman R C
Published: June 2011

A previous study in rats showed that even though probucol substantially lowers high density lipoprotein (HDL) levels, near-normal mass transport of HDL cholesterol esters (CE) to the liver is maintained by the induction of "selective" (direct) uptake of HDL CE. The present study describes a parallel result in cultured Hep G2 human hepatoma cells. Cells were preincubated in the presence or absence of probucol before measuring the uptake of doubly labeled HDL3 in the absence of probucol. Preincubation with probucol decreased the uptake of HDL3 particles (iodine-125-labeled N-methyltyramine cellobiose-apolipoprotein [125I-NMTC-apo] A-I uptake) but increased the uptake of [3H]cholesteryl oleyl ether in excess of 125I-NMTC-apo A-I (i.e., selective uptake) in a dose-dependent fashion. The reversibly cell-associated pool of CE tracer, a precursor for selective uptake, enlarged on probucol treatment, but the increase was not in proportion to the increase in selective uptake. HDL3 particle uptake decreased on probucol treatment. The decrease was evident after less than 20 minutes of probucol exposure and was maximal after 6 hours; in contrast, HDL3 CE selective uptake increased only after greater than 13 hours and had not reached a plateau after 20 hours. Thus, effects on particle uptake and selective uptake were dissociated in time.
Significant association between low-molecular-weight apolipoprotein(a) isoforms and intermittent claudication.
Authors: Mölgaard J , Klausen I C , Lassvik C , Faergeman O , Gerdes L U , Olsson A G
Published: June 2011

The role of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) isoforms in symptomatic peripheral atherosclerosis was studied in 100 randomly selected middle-aged (45-69 years) men with intermittent claudication (IC) and 100 randomly selected healthy control (C) subjects. IC and C subjects were matched pairwise for sex, age, and smoking habits. Plasma Lp(a) concentrations were significantly higher in IC subjects, with a median value of 20.12 mg/dl, compared with 11.11 mg/dl in C subjects (p less than 0.0009). The elevated Lp(a) concentration was to a great extent due to a significant difference in the frequency distribution of apo(a) isoforms between IC and C subjects (p less than 0.029). Low-molecular-weight apo(a) isoforms were more prevalent in IC than C subjects. Also, IC subjects with apo(a) S2 and S3 phenotypes had higher Lp(a) concentrations than control subjects with the same phenotypes: S2:60.70 mg/dl (IC) and 48.69 mg/dl (C), p less than 0.038; and S3: 30.18 mg/dl (IC) and 12.01 mg/dl (C), p less than 0.042, so other still-unknown factors, genetic or nongenetic, may be important. Stepwise logistic regression analysis demonstrated that Lp(a) concentration contributed significantly (p less than 0.0002) to IC, independent of age, smoking, hypertension, diabetes mellitus, plasma total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apo B, and plasma total triglycerides. Apo(a) isoforms grouped according to molecular weight were also independent of the above risk factors associated (p = 0.016) with the occurrence of IC because of their low-molecular-weight but were not independent of Lp(a) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis.
Authors: Jang I K , Gold H K , Leinbach R C , Fallon J T , Collen D , Wilcox J N
Published: June 2011

Activation of the coagulation system by contact of circulating blood with tissue factor, a component of the extrinsic blood coagulation pathway that is produced in the vessel wall, may represent a pathway for the initiation of thrombosis in atherosclerotic vessels. This hypothesis was tested in vivo in a rabbit femoral artery eversion (inside-out) graft model, in which the adventitia, with its tissue factor, was exposed to circulating blood. Intra-arterial infusion of a neutralizing monoclonal antibody against tissue factor (D3) at a rate of 12 mg/kg over 15 minutes prevented thrombosis of a 7-8-mm eversion graft within a 2-hour observation period in four of five rabbits, whereas with a control antibody infusion (MA-15C5), occlusion occurred within 2 hours in five of six rabbits. In vitro immersion before reinsertion of the arterial segment in a solution containing 2 mg/ml of the control antibody for 30 minutes was associated with occlusion in all six rabbits, whereas pretreatment with D3 was associated with persistent patency in three of nine rabbits. Stepwise logistic-regression analysis of the results with perfusion status as the dependent variable and type of antibody (D3 or MA-15C5), application method (infusion versus immersion), and graft segment length as independent variables yielded a significant difference in frequency of occlusion with the two antibodies (p = 0.016). It is concluded that exposure of tissue factor to flowing blood may constitute a trigger mechanism for platelet-mediated arterial thrombosis.
Role of the extracellular matrix in age-related modifications of the rat aorta. Ultrastructural, morphometric, and enzymatic evaluations.
Authors: Fornieri C , Quaglino D , Mori G
Published: June 2011

Connective tissues such as blood vessels are known to be greatly affected by age because of impaired functional properties and increased susceptibility to diseases. With the aim of providing further information on the role of the extracellular matrix in age-related modifications, we investigated the aorta in the rat model from birth to senescence by means of morphological and morphometric observations and by evaluation of lysyl oxidase activity. Results focused on the dramatic vascular rearrangements due to progressive fibrosis of the extracellular matrix and on prominent elastin modifications. The presence of lysyl oxidase activity, even in the oldest animals, might be at least partly responsible for the increased stiffness of the aging extracellular matrix. The striking age-related remodeling of the aortic architecture and the alterations of the interactions between cellular and extracellular compartments might greatly influence the functional properties of the arterial wall in senescence, at least contributing to the consequences of some apparently age-related vascular disorders.
Apo B insertion/deletion polymorphisms are associated with atherosclerosis in young black but not young white males. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.
Authors: Hixson J E , McMahan C A , McGill H C , Strong J P
Published: June 2011

Investigators in eight communities collected aortas, right coronary arteries, blood and liver samples, and associated information from 872 young males, aged 15-34 years, who died of external causes. Pathologists graded the arteries for atherosclerotic lesions, and a central laboratory measured lipoprotein cholesterol concentrations. Apolipoprotein (apo) B sequences were amplified in hepatic DNA samples to determine genotypes for length polymorphisms in the signal peptide of apo B. In addition to the insertion (ins) allele (27-amino acid signal peptide) and the deletion (del) allele (24 amino acids), we detected a rare allele (ins*) in whites with an in-frame insertion of two Leu codons in a region that normally contains six Leu codons. The frequency for the apo B del allele was lower in blacks than in whites (p less than 0.0001). In blacks, homozygotes for the ins allele had the lowest levels of serum cholesterol and very low plus low density lipoprotein cholesterol (VLDL + LDL-C), homozygotes for the del allele had the highest levels, and heterozygotes had intermediate levels (p = 0.0509 for cholesterol, p = 0.0530 for VLDL + LDL-C), but no differences were found in whites. In blacks, homozygotes for the ins allele had the least involvement of the thoracic and the abdominal aorta with lesions, homozygotes for the del allele had the greatest involvement, and heterozygotes had intermediate involvement (p = 0.0328 for thoracic aorta, p = 0.0104 for abdominal aorta), but no differences were found in whites.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of insulin resistance, secretion, and clearance on serum cholesterol, triglycerides, lipoprotein cholesterol, and blood pressure in healthy men.
Authors: Godsland I F , Crook D , Walton C , Wynn V , Oliver M F
Published: June 2011

Relations between serum lipids, lipoproteins, blood pressure, and insulin metabolism were investigated in 158 healthy men aged 19-77 years and with body mass indexes (BMIs) of 19-41 kg.m-2. Mathematical modeling analysis of glucose, insulin, and C-peptide concentrations during an intravenous glucose tolerance test was used to measure parameters of insulin metabolism. In univariate analysis, both fasting and postglucose insulin concentrations showed significant positive associations with fasting serum triglyceride levels (r = 0.33 and 0.38, respectively) and systolic (r = 0.22 and 0.26) and diastolic (r = 0.21 and 0.24) blood pressure and negative associations with high density lipoprotein subfraction 2 cholesterol (HDL2; r = -0.21 and -0.25). In multivariate analysis, the associations between insulin and HDL2 cholesterol concentrations were found to depend on triglyceride levels. Insulin resistance and basal pancreatic insulin secretion showed significant positive associations with serum triglycerides, which were independent of the effects of age, BMI, and fat distribution. Hepatic insulin throughout was independently associated with HDL2 cholesterol. Associations of insulin-related variables with blood pressure were generally dependent on age and BMI. These results underline the importance of insulin sensitivity and insulin concentrations as determinants of triglyceride metabolism. They also indicate a close relation between hepatic insulin handling and HDL2 concentration that is independent of triglyceride metabolism.
Inhibition of copper-mediated oxidation of LDL by rat serosal mast cells. A novel cellular protective mechanism involving proteolysis of the substrate under oxidative stress.
Authors: Lindstedt K A , Kokkonen J O , Kovanen P T
Published: June 2011

Rat serosal mast cells, when stimulated to exocytose their cytoplasmic granules, effectively blocked the copper-mediated oxidation of low density lipoproteins (LDLs) in vitro. This effect depended on the proteolytic activity of the formed extracellular granule remnants, since specific inhibition of chymase, the neutral protease that they contain, blocked the protective effect of the mast cells. The mechanism of this chymase-mediated inhibition of LDL oxidation was found to be binding of the copper ions present in the incubation medium by peptides released from LDL on proteolytic degradation of their apolipoprotein B (apoB) component. This was verified by demonstrating that addition of such peptides to LDL--copper ion mixtures completely prevented oxidation of LDL and that this protective effect could be overcome by adding copper ions in excess. Furthermore, proteolytic degradation of the apoB of LDL, with concomitant release of copper-containing peptides, left the partially degraded apoB without the copper ions necessary for propagation of LDL oxidation. These observations provide the first evidence for cell-mediated inhibition of LDL oxidation.
Arterial intimal hyperplasia after occlusion of the adventitial vasa vasorum in the pig.
Authors: Barker S G , Talbert A , Cottam S , Baskerville P A , Martin J F
Published: June 2011

Oxygenation of the arterial wall is provided by diffusion of oxygen outward from the main vessel lumen and inward from the adventitial vasa vasorum. In a group of four Yucatan miniature pigs the oxygenation profiles across the superficial femoral arteries were recorded by polarographic oxygen microelectrodes. The profiles obtained suggested a relatively poorly oxygenated media (a trough value of approximately 25% that of the intimal oxygenation) with a progressive rise in oxygenation toward the intimal and adventitial surfaces. In four other survival experiments, occlusion of the adventitial vasa vasorum by flush ligation of the arterial branches that supply them resulted in the production of a focal, intimal hyperplastic lesion that was absent in control vessels (intimal to medial ratios [mean +/- SEM] of 0.053 +/- 0.008, n = 8, p < 0.001 and 0.013 +/- 0.001, n = 8, respectively). By electron microscopy this lesion was seen to be composed mainly of smooth muscle cells. This evidence would support the hypothesis that arterial wall hypoxia may be involved in the initiation of intimal hyperplasia. It is proposed that human atherosclerosis may be initiated by occlusion of the vasa vasorum and concomitant hypoxia.
Inhibition of exercise-induced shortening of bleeding time by fish oil in familial hypercholesterolemia (type IIa).
Authors: Hansen J B , Lyngmo V , Svensson B , Nordøy A
Published: June 2011

Fourteen patients suffering from familial hypercholesterolemia (type IIa) participated in a double-blind, placebo-controlled trial that evaluated the effects of fish oil ethyl ester (K-85, 5.7 g/day) or a hydroxymethylglutaryl coenzyme A reductase inhibitor (lovastatin, 40 mg/day) alone or in combination on lipid metabolism and bleeding time at rest and after standardized exercise. Lovastatin treatment reduced total cholesterol (-27%), low density lipoprotein cholesterol (-37%), and triglycerides (-18%), whereas high density lipoprotein cholesterol increased significantly (14%). K-85 affected total (-4%), low density lipoprotein (-9%), and high density lipoprotein (+7%) cholesterol insignificantly, whereas the triglyceride level decreased by 24% (p < 0.001). The combined regimen caused an additive decrease in the triglyceride level (41%), which differed significantly (p < 0.01) from that gained by lovastatin alone. Under basal conditions the bleeding time was not influenced by the different interventions. Standardized exercise shortened the bleeding time by 19% (p < 0.001) and 16% (p < 0.001) before intervention and after lovastatin treatment, respectively. After K-85 alone or in combination with lovastatin, the exercise-induced shortening of the bleeding time was totally inhibited, which may reflect a favorable influence of fish oil on the platelet-vessel wall interaction in these high-risk patients.
Atherosclerotic changes in the femoral and carotid arteries in familial hypercholesterolemia. Ultrasonographic assessment of intima-media thickness and plaque occurrence.
Authors: Wendelhag I , Wiklund O , Wikstrand J
Published: June 2011

B-mode ultrasound is increasingly used in clinical research to study the atherosclerotic process in the carotid arteries. The present investigation evaluated the feasibility of measuring intima-media thickness in the common femoral artery and assessed whether such measurement might provide further information on the extent of the atherosclerotic process in patients with familial hypercholesterolemia. A further aim was to study the relationship between the intima-media thickness of the common carotid artery and the occurrence of plaque in the carotid and femoral arteries. The results showed an increased intima-media thickness in the far wall of the common femoral artery in patients with familial hypercholesterolemia compared with the control subjects (P < .01). The results also showed a clear relationship between the thickness of the intima-media complex in the common carotid artery and the prevalence of plaque in the carotid and femoral arteries. This may be interpreted as an indication that an increase in intima-media thickness in the common carotid artery at least partly expresses a generalized atherosclerotic process. The atherosclerotic changes appeared to be more advanced in the femoral artery compared with the carotid artery. In future studies, therefore, valuable information on different stages of atherosclerotic changes may be achieved by combining information from B-mode recordings from both the carotid and femoral arteries.
Plasma lipoprotein and apolipoprotein levels in Taipei and Framingham.
Authors: Lyu L C , Shieh M J , Ordovas J M , Lichtenstein A H , Wilson P W , Schaefer E J
Published: June 2011

We compared the plasma lipoprotein cholesterol, triglyceride, apolipoprotein (apo) A-I, apoB, and lipoprotein(a) [Lp(a)] concentrations in a low coronary heart disease (CHD) risk population (n = 440) in Taipei with a high CHD risk population (n = 428) in Framingham matched for age, sex, and menopausal status. Taipei men had significantly lower low-density lipoprotein cholesterol (LDL-C) (-20 mg/dL, -14%, P < .01) and apoB (-7 mg/dL, -6%, P < .05) levels and significantly higher high-density lipoprotein cholesterol (HDL-C) levels (6 mg/dL, 13%, P < .01) than Framingham men. Taipei women had significantly lower LDL-C (-18 mg/dL, -15%, P < .01) and higher HDL-C (4 mg/dL, 7%, P < .01) levels than Framingham women. Median concentrations and distributions of Lp(a) by sex were similar in Taipei and Framingham. After adjusting for body mass index and smoking status, only differences in total cholesterol and LDL-C levels remained significantly different for both sexes between the two populations (P < .01). Gender differences for lipids within populations were similar. After adjusting for age, body mass index, and smoking status, women in both Taipei and Framingham had significantly lower mean triglyceride, LDL-C, and apoB levels and significantly higher HDL-C and apoA-I levels than men. Postmenopausal women in Taipei had significantly higher mean total cholesterol, LDL-C, HDL-C, apoA-I, apoB, and Lp(a) levels than premenopausal women (P < .05), whereas in Framingham postmenopausal women had significantly higher total cholesterol, triglyceride, LDL-C, and apoB levels than premenopausal women (P < .05). Our data are consistent with the concept that plasma lipoprotein cholesterol levels (especially LDL-C) but not apolipoprotein values explain some of the twofold difference in age-adjusted CHD mortality between these two populations.
Phenotypic variation among familial hypercholesterolemics heterozygous for either one of two Afrikaner founder LDL receptor mutations.
Authors: Kotze M J , De Villiers W J , Steyn K , Kriek J A , Marais A D , Langenhoven E , Herbert J S , Graadt Van Roggen J F , Van der Westhuyzen D R , Coetzee G A
Published: June 2011

Two common founder-related gene mutations that affect the low-density lipoprotein receptor (LDLR) are responsible for approximately 80% of familial hypercholesterolemia (FH) in South African Afrikaners. The FH Afrikaner-1 (FH1) mutation (Asp206-->Glu) in exon 4 results in defective receptors with approximately 20% of normal activity, whereas the FH Afrikaner-2 (FH2) mutation (Val408-->Met) in exon 9 completely abolishes LDLR activity (< 2% normal activity). We analyzed the contribution of these mutations and other factors on the variation of hypercholesterolemia and clinical features in Afrikaner FH heterozygotes. The type of FH mutation, plasma triglyceride levels, and age of patients each contributed significantly to the variation in hypercholesterolemia, whereas smoking status, high-density lipoprotein cholesterol levels, and gender had no influence. Although all FH heterozygotes had frank hypercholesterolemia, patients with the FH1 mutation had significantly lower cholesterol levels than those with the FH2 mutation. FH1 heterozygotes also tended to have milder clinical features. The differences between the two FH groups could not be explained by a difference in the common apolipoprotein E variants. This study demonstrates that mutational heterogeneity in the LDLR gene influences the phenotypic expression of heterozygous FH.
Protein kinase C inhibitors prevent impairment of endothelium-dependent relaxation by oxidatively modified LDL.
Authors: Ohgushi M , Kugiyama K , Fukunaga K , Murohara T , Sugiyama S , Miyamoto E , Yasue H
Published: June 2011

The mechanism(s) of inhibition of endothelium-dependent relaxation (EDR) by oxidized low-density lipoprotein (Ox-LDL) was examined in isolated porcine coronary arteries and rabbit aortas. Incubation with Ox-LDL but not native LDL caused the inhibition of thrombin- or acetylcholine-induced EDR, whereas A23187-induced EDR was preserved after incubation with Ox-LDL. Lysophosphatidylcholine (lysoPC), which was abundant in Ox-LDL and was found to be transferred from Ox-LDL to endothelial cells, also caused the inhibition of EDR in response to thrombin or acetylcholine but not to A23187. Ox-LDL depleted of lysoPC, which was prepared by phospholipase B, failed to inhibit the vasorelaxation. Coincubation with staurosporine or calphostin C, potent inhibitors of protein kinase C, attenuated the EDR inhibition by Ox-LDL or lysoPC. Phorbol 12-myristate 13-acetate, a specific protein kinase C activator, caused the EDR inhibition, and its effect was attenuated by staurosporine or calphostin C. Furthermore, lysoPC was capable of activating protein kinase C purified from cultured porcine endothelial cells. In conclusion, protein kinase C activation plays a role in the inhibition of surface receptor-mediated EDR by Ox-LDL, and lysoPC transferred from Ox-LDL to endothelial cells may be involved in the activation of protein kinase C.
Intact platelet membranes, not platelet-released microvesicles, support the procoagulant activity of adherent platelets.
Authors: Swords N A , Tracy P B , Mann K G
Published: June 2011

The possibility that platelets release microvesicles on adherence to either von Willebrand factor (vWf) or collagen was examined by flow cytometry analysis of the supernatant above layers of adherent platelets. No microvesicle release was detected as a result of adherence to vWf or to collagen, a known platelet agonist. Approximately 8% of the total platelet mass was released as microvesicles after thrombin stimulation of the vWf- or collagen-adherent platelets. A larger portion of the vWf-adherent platelet membranes (approximately 21%) was released as microvesicles subsequent to platelet stimulation with the nonphysiological agonist calcium ionophore A23187. Calpeptin, a calpain inhibitor, had no effect on microvesicle release, suggesting that calpain proteolysis of platelet cytoskeletal proteins was not responsible for microvesicle shedding under the conditions studied. Examination of the vWf-adherent platelets by scanning electron microscopy showed that virtually no microvesicles bound to exposed vWf multimers. No microvesicle binding to the adherent platelets was observed, indicating that the majority of the microvesicles were shed from the platelet and vWf surface on platelet activation. The ability of the microvesicle population to support procoagulant activity was measured with a prothrombinase activity assay and was compared with the activity supported by the adherent platelet membranes. More than 85% of the total prothrombinase activity remained associated with the adherent platelet membranes, both for unstimulated platelets and platelets stimulated with physiological agonists. Furthermore, the residual activity found in the buffer fraction containing detached platelets and any released microvesicles could be attributed to the detached platelets. No activity could be attributed to the microvesicles, as thrombin stimulation of either vWf-or collagen-adherent platelets did not promote increased procoagulant activity relative to the unstimulated adherent platelets, even though microvesicle release was detected as a result of agonist addition. Neither full platelet activation nor microvesicle shedding played an essential role in generating procoagulant activity in the adherent platelet system.
Cytokeratins 8 and 18 in smooth muscle cells. Detection in human coronary artery, peripheral vascular, and vein graft disease and in transplantation-associated arteriosclerosis.
Authors: Jahn L , Kreuzer J , von Hodenberg E , Kübler W , Franke W W , Allenberg J , Izumo S
Published: June 2011

During development of atherosclerotic lesions, vascular smooth muscle cells (SMCs) undergo changes both phenotypically and in their cytoskeleton composition. An expression of cytokeratins 8 and 18 in SMCs in plaques of the human superficial femoral artery and of cytokeratin 8 in lesions of the aorta was recently described. Since cytokeratins are epithelial markers generally not found in normal adult vascular SMCs, we performed a detailed immunofluorescence microscopy study using a large panel of antibodies against the various cytokeratin polypeptides and other elements of the cytoskeleton. We included lesions of carotid, common and superficial femoral, iliac, and popliteal arteries; the abdominal aorta; and saphenous vein bypass grafts, as well as primary, restenotic, and transplantation-associated lesions of coronary arteries (n = 33). Cytokeratins 8 and 18 were present in myointimal cells of all pathological specimens. Colocalization with smooth muscle alpha-actin identified most cytokeratin-positive cells as SMCs. Only very few cells cosynthesized cytokeratin and desmin, whereas the majority of cytokeratin-positive cells were vimentin-positive. This pattern of cytoskeletal protein synthesis is similar to that found in some fetal and/or neonatal SMCs. These findings suggest that the synthesis of cytokeratins in a subset of SMCs of atherosclerotic lesions is a common phenomenon in coronary artery and peripheral vascular disease as well as graft disease and transplantation-associated arteriosclerosis and that the state of these SMCs is of a "dedifferentiated" fetal type.
Human type II hyperlipoproteinemia enhances platelet-collagen adhesion in flowing nonanticoagulated blood.
Authors: Cadroy Y , Lemozy S , Diquélou A , Ferrières J , Douste-Blazy P , Boneu B , Sakariassen K S
Published: June 2011

We investigated the effects of high plasma lipid levels on platelet adhesion and platelet thrombus formation in nonanticoagulated human blood on collagen fibrils at an arterial wall shear rate of 2600 seconds-1. Nonanticoagulated blood was drawn directly at a flow rate of 10 mL/min for 3 minutes from an antecubital vein of patients with type IIa (n = 5) and type IIb (n = 4) hyperlipoproteinemia over purified human type III collagen fibrils that were positioned on a plastic coverslip in a parallel-plate perfusion chamber. Results were compared with those obtained in healthy individuals with normal lipid plasma levels (n = 9). Blood-collagen interactions were quantified by morphometry as platelet-collagen adhesion, thrombus volume, and fibrin deposition. Platelet-collagen adhesion in the two groups of patients was significantly higher than in healthy individuals (70.7 [61.2 to 82.0] and 70.3 [66.4 to 81.0] in types IIa and IIb patients, respectively, versus 51.2 [44.5 to 68.6] in control subjects; P < .05. All values are percent median [range]). In contrast, the thrombus volume was similar in the three groups (11.3 [8.0 to 13.0], 9.6 [6.4 to 15.3], and 10.2 [6.8 to 16.1] microns3/microns2 [range], respectively). Differences in fibrin deposition were not observed. Thus, it appears that platelet-collagen adhesion is augmented in patients with type IIa and IIb hyperlipoproteinemia, indicating that the process of thrombogenesis is hastened in these patients.
Lysophosphatidic acid enhances fibronectin binding to adherent cells.
Authors: Checovich W J , Mosher D F
Published: June 2011

1-Oleoyl lysophosphatidic acid (LPA) enhanced binding of 125I-labeled fibronectin by cultured MG-63 osteosarcoma cells and human fibroblasts in monolayer cultures up to threefold over control levels. For osteosarcoma cells, LPA was minimally active at 0.1 ng/mL (0.2 nmol/L) and reached maximal activity at 10 ng/mL (20 nmol/L). Increased binding was evident within 10 minutes of treatment of cycloheximide-treated cells with LPA and was due to an increase in the number of fibronectin binding sites. LPA also increased the binding of a fragment containing the 70-kDa amino-terminal region of fibronectin that is primarily responsible for the reversible binding of fibronectin to matrix assembly sites on cell surfaces. Removal of LPA resulted in prompt return of fibronectin binding to baseline levels. These results indicate that LPA is an important enhancer of fibronectin-rich matrix deposition by cultured cells, and it may be the active component in serum and lipoprotein fractions that is responsible for enhancing fibronectin deposition.
Benzo(a)pyrene enhances atherosclerosis in White Carneau and Show Racer pigeons.
Authors: Hough J L , Baird M B , Sfeir G T , Pacini C S , Darrow D , Wheelock C
Published: June 2011

Benzo(a)pyrene (BaP), a major environmental pollutant and component of cigarette smoke, is both carcinogenic and atherogenic in experimental models. We investigated the effect of long-term administration of BaP on atherogenesis in both atherosclerosis-susceptible White Carneau (WC) and atherosclerosis-resistant Show Racer (SR) pigeons. The number and size of arterial lesions in the brachiocephalic arteries in WC and SR females but not males were significantly enhanced after long-term dosing with BaP. Metabolic activation appears to be required for BaP atherogenicity, since benzo(e)pyrene (BeP), a noncarcinogenic analogue of BaP, did not enhance lesion development. Studies with 3H-BaP revealed no significant differences between male and female or between WC and SR pigeons in the arterial distribution of BaP and/or its metabolites. There were no consistent differences in blood pressure or plasma cholesterol levels between breeds or sexes. However, chronic administration of BaP did result in complete infertility in female birds, concomitant with grossly visible changes in ovarian appearance. These results clearly show that long-term dosing with BaP alters ovarian structure and function in treated birds, at the same time aggravating the development of arterial lesions. Thus, BaP-induced atherogenicity in female pigeons may be a consequence of an alteration in estrogen production or of antiestrogenic properties of BaP at the level of the arterial wall and may serve as a highly useful animal model to examine the well-known rapid development of atherosclerosis in postmenopausal women.
Effects of local geometry and fluid dynamics on regional platelet deposition on artificial surfaces.
Authors: Schoephoerster R T , Oynes F , Nunez G , Kapadvanjwala M , Dewanjee M K
Published: June 2011

An important aspect of blood-material interactions is the activation, adhesion, and subsequent aggregation of blood platelets on the artificial surface, all of which are directly affected by local fluid dynamics. The objective of this work was to directly correlate changing local fluid dynamic conditions produced by various vessel geometries, including stenosis, aneurysm, and separate contraction and expansion geometries, with quantitative in vitro measurements of regional platelet deposition. We directly measured platelet deposition as a function of axial position along four Lexan flow chambers with axisymmetric models of these geometries using 111In-labeled platelets. Platelet deposition was maximum in observed areas of flow recirculation and reattachment and minimum in locations of high shear and separation. For the stenosis geometry, two distinct regions of increased platelet deposition were apparent, one proximal to and one distal to the stenosis throat. An approximately linear increase in platelet densities was produced in the aneurysm region, increasing in the direction of flow. Through a comparison of platelet deposition with local fluid streamline orientation, we have shown that platelet deposition is increased in certain areas due to the enhanced convective transport of platelets and blood cells to the vessel wall along locally curved streamlines with velocity components perpendicular to the vessel wall.
Effect of vitamin E on vascular integrity in cholesterol-fed guinea pigs.
Authors: Qiao Y , Yokoyama M , Kameyama K , Asano G
Published: June 2011

This study was designed to clarify the effects of vitamin E on the alterations in proteoglycan distribution and vascular permeability, which were examined by immunohistochemical and ultrastructural techniques in the aortas of cholesterol-fed guinea pigs. The animals were divided into three groups: a control group, a cholesterol group, and a vitamin E group. Serum levels of cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein, and thiobarbituric acid-reactive substances were measured. An increase in thiobarbituric acid-reactive substances was observed in the cholesterol group compared with control and vitamin E groups. Intimal atheromatous lesions of the aorta were significantly decreased in the vitamin E group compared with the cholesterol group. Histochemically, an increased distribution of proteoglycans such as chondroitin, dermatan, and heparan sulfates and ruthenium red reaction products in the intima; decreased glycocalyx on the endothelial surface; and increased permeability to horseradish peroxidase were revealed in the cholesterol group compared with the vitamin E group. Hypercholesterolemia, resulting in superoxide production, may have contributed to the endothelial damage and increased permeability to plasma proteins and lipids in the vascular wall of the cholesterol group. However, vitamin E administration inhibited lipid deposition and development of this abnormal permeability associated with an irregular distribution of proteoglycan. These results suggest that vitamin E preserves the morphological and functional integrity of the vascular wall and may contribute to the inhibition of atherogenesis in cholesterol-fed guinea pigs.
Effect of hepatic lipase on LDL in normal men and those with coronary artery disease.
Authors: Zambon A , Austin M A , Brown B G , Hokanson J E , Brunzell J D
Published: June 2011

Hepatic triglyceride lipase (HL) is thought to play a role in the formation of low density lipoproteins (LDLs) from small very low density lipoproteins (VLDLs) and intermediate density lipoproteins (IDLs). To analyze the possible physiological role of HL in determining LDL buoyancy, size, and chemical composition, HL activity and LDL were studied in 21 patients with coronary artery disease (CAD) and 23 normolipidemic subjects. In both groups, LDL buoyancy and size were inversely associated with HL activity levels. The effect of HL on LDL size was comparable in CAD patients and in normolipidemic subjects. HL appeared to influence LDL lipid composition primarily by affecting the surface lipid components. The free cholesterol content of LDL particles was highly correlated with HL activity in both CAD and normolipidemic individuals. The free cholesterol to phospholipid ratio in LDL particles correlated with HL in both CAD and normolipidemic subjects. When the individuals were separated according to their LDL subclass patterns, pattern B subjects had significantly higher HL than pattern A subjects in both CAD and normolipidemic groups. The analysis of the cholesterol distribution profiles across the lipoprotein density gradient confirmed that LDL buoyancy is affected by HL. These data support the hypothesis that HL modulates the physical and compositional properties of LDL and contributes to the expression of the LDL subclass phenotype, suggesting a physiological role for HL in LDL metabolism.
Cardiovascular risk factors in non-insulin-dependent diabetic subjects with microalbuminuria.
Authors: Haffner S M , Morales P A , Gruber M K , Hazuda H P , Stern M P
Published: June 2011

In subjects with insulin-dependent diabetes mellitus, microalbuminuria has been associated with increased triglyceride and lipoprotein (a) (Lp[a]) concentrations and increased blood pressure. However, few studies have examined whether this association is present in subjects with non-insulin-dependent diabetes mellitus (NIDDM). We measured lipids, lipoproteins, Lp(a), blood pressure, and albumin excretion in 234 subjects with NIDDM from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Seventy-two subjects had microalbuminuria (> or = 30 mg/dl). These subjects had increased systolic and diastolic blood pressures and higher fasting glucose concentrations relative to subjects without microalbuminuria. However, there were no significant differences between subjects with and without microalbuminuria with respect to lipids, lipoproteins, Lp(a), self-reported myocardial infarction, obesity, or body fat distribution. Subjects with diabetic retinopathy had increased microalbuminuria. In multivariate analysis both glycemia and blood pressure continued to be significantly related to the presence of microalbuminuria. We conclude that NIDDM subjects with microalbuminuria have elevated blood pressure and more severe glycemia but do not have a significantly more atherogenic pattern of lipids, lipoproteins, or Lp(a) than subjects without microalbuminuria.
Human cholesterol synthesis measurement using deuterated water. Theoretical and procedural considerations.
Authors: Jones P J , Leitch C A , Li Z C , Connor W E
Published: June 2011

Human cholesterogenesis is measurable as the rate of incorporation of deuterium derived from deuterium oxide (D2O) within the body water pool into plasma or erythrocyte cholesterol pools. Oral D2O equilibrates across body water, thus enabling extracellular sampling of pools (such as urine) to serve as accurate indicators of intracellular deuterium enrichments at the point of synthesis. Required doses of D2O fall below the threshold associated with negative side effects. Deuterium/carbon incorporation ratios into cholesterol during biosynthesis have been established that are applicable in humans. Models using unconstrained and constrained curve fitting permit improved flexibility in interpretation of deuterium-uptake kinetics. However, sample-size restrictions presently limit the ability of the technique to examine the kinetics within individual lipoprotein species. Correction of enrichment data for proton exchange during combustion and reduction phases of sample preparation is an additional important procedural concern. In summary, the deuterated-water procedure is a useful tool in studies of human cholesterol synthesis that offers the advantages of short measurement interval, relative noninvasiveness, and provision of a direct index of synthesis in comparison with other available techniques.
Protection from atherosclerosis in vein grafts by a rigid external support.
Authors: Batellier J , Wassef M , Merval R , Duriez M , Tedgui A
Published: June 2011

Atherosclerosis is a common feature of autogenous vein bypass grafts resulting in their long-term failure. Arterial pressure-induced distension is thought to play a major role in the wall thickening of vein grafts, which may in turn favor atherosclerotic complications. In this study, we evaluated the influence of vein distension on the development of atherosclerotic lesions in jugular vein grafts interposed into the common carotid arteries of rabbits. The proximal half of each vein graft was wrapped with a 4-mm-diameter polytetrafluoroethylene graft that reduced the vein graft diameter by 46 +/- 5%. Fourteen animals were fed a 1% cholesterol-rich diet for 8 weeks, and five animals were fed a normal diet. In normocholesterolemic and hypercholesterolemic animals, the wall thickness and the total cross-sectional area were significantly reduced in wrapped compared with unwrapped segments. Foam cells were never observed in normocholesterolemic animals. In hypercholesterolemic rabbits, the sudanophilic lesions covered 62 +/- 4% of the luminal surface in unwrapped segments and 31 +/- 7% in wrapped segments (p < 0.0001). In transverse sections, the surface areas of foam cells were also markedly reduced in wrapped compared with unwrapped segments. Reduction of the wall distension using a rigid external support protected the vein grafts from atherosclerosis, possibly as a result of the decrease in wall thickening that occurred in response to arterialization.
Visceral fat loss measured by magnetic resonance imaging in relation to changes in serum lipid levels of obese men and women.
Authors: Leenen R , van der Kooy K , Droop A , Seidell J C , Deurenberg P , Weststrate J A , Hautvast J G
Published: June 2011

The effect of weight reduction on serum lipids in relation to visceral fat accumulation was studied in 78 healthy obese subjects (40 premenopausal women and 38 men) aged 27-51 years and with an initial body mass index of 30.7 +/- 2.2 kg/m2 (mean +/- SD). The subjects received a 4.2 MJ/day energy-deficit diet for 13 weeks. Magnetic resonance imaging was used to assess abdominal fat areas before and after weight loss. Weight reductions of 12.6 +/- 3.2 kg in men and 11.7 +/- 3.8 kg in women resulted in larger reductions in the fasting serum levels of total cholesterol (p < 0.05), low density lipoprotein cholesterol (p = 0.06), and triglycerides (p < 0.01) and a larger increase in the high density lipoprotein cholesterol/low density lipoprotein cholesterol ratio (p = 0.05) in men compared with women. Men also lost more visceral fat (p < 0.0001), whereas the reductions in the total and subcutaneous abdominal fat depots were similar. In women, visceral fat loss was significantly related with an increase of the high density lipoprotein cholesterol level, independent of the degree of total fat loss. In men, however, no significant correlations were observed between changes in visceral fat and any of the serum lipids. Comparisons of average changes in obese men and women suggest that visceral fat loss is associated with an improvement of the serum lipid profile. However, correlation analysis does not support a critical role of visceral fat in determining serum lipid concentrations on an individual level, except for an improvement of the high density lipoprotein cholesterol level with visceral fat loss in obese women.
Increased postprandial lipemia in Apo A-IMilano carriers.
Authors: Calabresi L , Cassinotti M , Gianfranceschi G , Safa O , Murakami T , Sirtori C R , Franceschini G
Published: June 2011

Plasma lipid/lipoprotein changes were monitored after a fat load (65 g fat per square meter body surface area) in six carriers of the apolipoprotein A-IMilano (A-IM) variant and six age- and sex-matched control subjects. The magnitude of postprandial lipemia, calculated as the area under the curve (AUC) described by plasma triglyceride (TG) level versus time, was threefold higher in the A-IM carriers; however, after correction for the different baseline TG levels, it was similar to control subjects. Moreover, the magnitude of postprandial lipemia was positively correlated with baseline TG in both A-IM carriers (r = 0.77) and control subjects (r = 0.80), indicating that fasting TGs are a major determinant of postprandial response in all subjects. Postprandial lipemia was also inversely correlated with high density lipoprotein (HDL) and HDL2 cholesterol in both groups (A-IM, r = -0.81 and -0.79; control subjects, r = -0.87 and -0.94). Different from those in control subjects, the plasma apo A-I levels in the A-IM carriers decreased progressively while apo B increased up to 4 hours but decreased thereafter. Postprandial rises of low density lipoprotein TG but not of HDL-TG AUC were significantly higher in the A-IM carriers, even after normalization for the different fasting concentrations. These data show that the low plasma HDL levels of A-IM carriers, which are secondary to a primary structural alteration of the major HDL apolipoprotein, are associated with elevated fasting and postprandial TG levels and an anomalous postprandial redistribution of TG among lipoprotein classes.