Arteriosclerosis and Thrombosis: A Journal of Vascular Biology

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ISSN / EISSN : 1049-8834 / 1049-8834
Total articles ≅ 853
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S L Diamond, F Sachs, W J Sigurdson
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 2000-2006; https://doi.org/10.1161/01.atv.14.12.2000

Abstract:
We sought to evaluate the mechanisms by which mechanical perturbation elevates intracellular calcium in endothelial cells. We report that the transient elevation in intracellular calcium in cultured bovine aortic endothelial cells (BAEC) in response to gentle perturbation with the side of a micropipette was not blocked by depolarization (external K+, 130 mmol/L), nifedipine (10 mumol/L), or Bay K 8644 R(+) (10 mumol/L). Thus, voltage-dependent calcium channels were not involved in the response. Also, amiloride (10 mumol/L) and tetraethylammonium (1 mmol/L) had no effect on calcium mobilization, indicating that Na+ and K+ transporters were not involved. Pretreatment of the cells with the phospholipase C and phospholipase A2 inhibitor manoalide (10 mumol/L) for 10 minutes at 37 degrees C completely abolished the calcium response, as did a 10-minute pretreatment with the inhibitor of actin polymerization, cytochalasin B (1 mumol/L). We observed an inhibitory effect of the phospholipase A2 and phospholipase C inhibitor 4-bromophenacyl bromide (10 mumol/L) on the mechanical response of BAEC that was not as potent as that observed with manoalide. To examine the role of arachidonic acid (AA) and subsequent metabolites that may be released after a putatively mechanical activation of phospholipase A2, we exposed BAEC to exogenous AA. We found that continued exposure of BAEC for 5 minutes to 10 nmol/L to 10 mumol/L AA caused no elevation of intracellular calcium. If mechanical stimulation activates phospholipase A2, the liberated AA and subsequent metabolites do not appear to have much effect on BAEC intracellular calcium.(ABSTRACT TRUNCATED AT 250 WORDS)
N Saha, Y Liu, , S Hong, P S Low, J S Tay
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1923-1927; https://doi.org/10.1161/01.atv.14.12.1923

Abstract:
Plasma factor VII activity (factor VIIc) is one of the independent risk factors for coronary artery disease and is controlled by both genetic and environmental factors. Several studies in healthy Caucasian subjects have revealed an association of a common genetic polymorphism at residue 353 (Arg-->Gln) of the factor VII gene with plasma factor VIIc. We have investigated the influence of this polymorphism (factor VII Arg/Gln353) on fasting plasma factor VIIc and antigen (factor VIIag) levels and its interaction with triglyceride levels in 185 healthy Dravidian Indians of both sexes (128 men, 57 women). The frequency of Gln353 has been found to be significantly higher in Dravidian Indians (0.29; confidence interval, 0.27 to 0.30) than in Caucasians (0.10). The distribution of factor VII Arg/Gln353 genotypes was at Hardy-Weinberg equilibrium. The carriers of the Gln353 allele had significantly lower plasma factor VIIc and factor VIIag in men (P < .05). The factor VII Arg/Gln353 polymorphism explained 13% and 11% of the total variance of plasma factor VIIc and factor VIIag, respectively, in men (P < .001) and 6% and 9% in women (P > .1). The genotype-specific correlation of factor VIIc and factor VIIag with triglyceride levels was stronger in carriers of the Gln353 allele (r = .38 and .41; P < .001) than in Arg353 homozygotes (r = .09 and .27; P = .19 and .005, respectively).
W H Sutherland
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1966-1975; https://doi.org/10.1161/01.atv.14.12.1966

Abstract:
Oxidation of low-density lipoprotein (LDL) in the artery wall is probably determined by several factors, some of which may include physiological oxidants such as heme and hydrogen peroxide, blood serum components, and the interaction of the lipoprotein with glycosaminoglycans. Glycosaminoglycans form complexes with LDL that increase its susceptibility to oxidation in vitro. To examine the effect of these factors on oxidation of LDL from serum by using heparin and oxidized the resolubilized lipoprotein (Hep-LDL) with hemin and hydrogen peroxide in the presence of apolipoprotein B lipoprotein-deficient serum (BLPDS). Low levels (2.1%) of BLPDS stimulated the oxidation of Hep-LDL by approximately fivefold, and increasing concentrations reduced oxidation to baseline rates. By comparison, the oxidation of native LDL was stimulated to a similar extent at lower concentrations of BLPDS (0.83%) and returned to baseline more rapidly with increasing levels of the serum fraction. Oxidation rates did not change significantly with increasing concentrations of BLPDS alone. Human serum albumin (HSA) at comparable levels produced changes in the oxidation of Hep-LDL similar to those seen with BLPDS. Degradation of heme was accelerated by low levels of BLPDS or HSA in the presence of hydrogen peroxide but not by higher levels, and maximal degradation rates were inhibited by comparatively low levels of butylated hydroxytoluene (35 mumol/L). This antioxidant also effectively inhibited oxidation of Hep-LDL maximally stimulated by BLPDS. The data suggest that serum components, particularly HSA, modulate the peroxidation of both glycosaminoglycan-treated LDL and native LDL by hemin and hydrogen peroxide via mechanisms that may involve oxidative interactions between heme and HSA. This phenomenon may influence oxidation of LDL in vivo, where levels of HSA in regions of the artery wall are comparable with levels that stimulate the oxidation of Hep-LDL in vitro.
M Benezra, S A Ben-Sasson, J Regan, M Chang, R Bar-Shavit, I Vlodavsky
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1992-1999; https://doi.org/10.1161/01.atv.14.12.1992

Abstract:
Proliferation of bovine aortic smooth muscle cells (SMCs) induced by thrombin, basic fibroblast growth factor, or serum is inhibited by anionic, nonsulfated aromatic compounds that mimic many of the effects of heparin. Among these compounds are aurintricarboxylic acid (ATA) and a newly synthesized polymer of 4-hydroxyphenoxy acetic acid (compound RG-13577). Iodinated- or 14C-labeled compound RG-13577 binds to cultured SMCs in a highly specific and saturable manner. Scatchard analysis of the binding data revealed the presence of an estimated 1 x 10(7) binding sites per cell with an apparent dissociation constant of 3 x 10(-6) mol/L. Binding of radiolabeled RG-13577 was efficiently competed for by related aromatic anionic compounds and by apolipoprotein E, but not by heparin, heparan sulfate, suramin, or various purified growth factors and extracellular matrix proteins. Receptor cross-linking of SMC-bound 125I-RG-13577 revealed a single species of high M(r) (approximately 280 kD) cell surface receptors detected in the absence but not the presence of excess unlabeled compound RG-13577. Binding was susceptible to downregulation and restoration of receptor levels in a manner similar to that of hormone and growth factor receptors. We suggest that the antiproliferative activity of compound RG-13577 and related compounds is initiated by binding to specific growth-inhibiting cell surface receptors. Heparin-mimicking compounds may be applied to inhibit SMC proliferation associated with atherosclerosis and restenosis.
J. Emmerich, D. Vidaud, M. Alhenc-Gelas, G. Chadeuf, M. Gouault-Heilmann, M. F. Aillaud, M. Aiach
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1958-1965; https://doi.org/10.1161/01.atv.14.12.1958

Abstract:
We have identified three novel mutations of the antithrombin (AT) gene in patients with thrombotic complications: a Cys 128 --> Tyr mutations, a G --> A mutation in the intervening sequence 4 (IVS4) 14 nucleotide 5' to exon 5, and a 9 bp deletion in the 3' end of exon 6 resulting in a short aberrant sequence after Arg 425. The latter mutation was associated with an Arg 47 --> His mutation in two compound heterozygous brothers. These three mutations led to the expression in the circulation of small amounts of inactive molecules with a high molecular mass in immunoblot analysis. In reducing conditions, these variant molecules had a normal molecular mass, which led us to postulate that these mutations prevent the formation of one intramolecular disulfide bond and allow the formation of intermolecular disulfide bonds. Plasma from a heterozygous patients bearing the Cys 128 --> Tyr mutation and from a compound heterozygote bearing the Arg 47 --> His mutation and the 9 bp deletion in exon 6 were passed through a heparin-sepharose column. In both cases a population of high-molecular-weight AT molecules with no binding affinity and no AT activity was separated from a population of normal molecules in the first patient, together with a population of molecules with a reduced binding affinity for heparin due to the substitution of Arg 47, in the compound heterozygote. The common feature of these three mutations is that they lead to partial misfolding and to the formation of intermolecular disulfide bonds with other plasma components, inducing the pleiotropic phenotypes observed.
J F Toussaint, J F Southern, , H L Kantor
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1951-1957; https://doi.org/10.1161/01.atv.14.12.1951

Abstract:
Previous investigations have used 13C-nuclear magnetic resonance (NMR) spectroscopy to demonstrate the similarities between lipoproteins and the mobile lipids of atheroma. In this study, we tested the hypothesis that 13C-NMR changes are related to indices of histological severity. We classified 20 human arteries according to their obstruction ratio (OR), defined as the ratio of the plaque area to the area delimited by the external elastic lamina. In group A, OR was < 40%, and in group B, OR was > 40%. We analyzed at 9.4 T the resonances of unsaturated (UFA) and polyunsaturated (PUFA) carbons, the resonances of the carbons 19 and 21 (C19, C21) of cholesteryl esters (CE), the methine carbon peak of fatty acids (CH2)n, the choline peak from phospholipids (PL), and the glycerol peak from triglyceride (TG). The UFA/PUFA, UFA/(CH2)n, and PUFA/(CH2)n ratios are markers of fatty acid saturation. (C19, C21)/(CH2)n, choline/(CH2)n, and glycerol/(CH2)n are indices of CE, PL, and TG content, respectively. UFA/PUFA in group A is 1.15 +/- 0.34 versus 1.63 +/- 0.32 in group B (P = .005). PUFA/(CH2)n is 0.26 +/- 0.10 in group A versus 0.16 +/- 0.04 in group B (P = .049). C19, C21/(CH2)n in group A is 0.32 +/- 0.15 versus 0.63 +/- 0.23 for group B (P = .003). No significant difference was found in UFA/(CH2)n or in the TG or PL ratios. 13C spectral examination of human atherosclerosis demonstrates decreased resonances for polyunsaturated fatty acyl chains and cholesteryl esters with increasing obstruction.
R. Romling, A. Von Eckardstein, H. Funke, C. Motti, G. C. Fragiacomo, G. Noseda, G. Assmann, Tineke J. Smilde, Franchette W. P. J. Van Den Berkmortel, Godfried H. J. Boers, et al.
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1915-1922; https://doi.org/10.1161/01.atv.14.12.1915

Abstract:
Conflicting data from epidemiological trials, genetic family studies, transgenic animal models, and in vitro experiments have created controversy regarding the importance of HDL and apolipoprotein (apo) A-I for reverse cholesterol transport and protection from atherosclerosis. In this study we identified a homozygous nonsense mutation in codon 32 (Q32X) of the apoA-I gene as the molecular basis of apoA-I deficiency in a 31-year-old woman who did not present with clinical signs of atherosclerosis. Despite half-normal plasma concentrations of HDL cholesterol and apoA-I in subjects heterozygous for this mutation, the history of the patient's large family did not indicate any increased prevalence of myocardial infarction.
R M Barstad, H E Roald, Y Cui, V T Turitto, K S Sakariassen
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1984-1991; https://doi.org/10.1161/01.atv.14.12.1984

Abstract:
The precipitating event leading to stroke, myocardial infarction, and/or sudden death may be related to the formation of mural thrombus at the site of a ruptured or superficially damaged stenotic plaque. The fluid dynamic properties at atherosclerotic plaques that may be implicated in this thrombus formation have been described in a wide variety of model systems in both the process of plaque rupture and the growth of platelet thrombi. In general, the local fluid dynamic conditions are complex and show major variations from flow in well-defined laminar flow systems. However, no studies have attempted to quantify the effect of stenosis-related disturbances on thrombus formation in native human blood and to compare them with the local fluid dynamics. We developed a parallel-plate perfusion chamber device in which thrombus formation is measured at the "apex" of eccentric stenoses and have correlated such measurements with values of the local fluid dynamics obtained by computer simulation. The extent of stenoses (reduction in the cross-sectional area of the blood flow channel) was 60%, 80%, and 89%, corresponding to "apex" wall shear rates of 2600, 10,500, and 32,000 sec-1, respectively. The wall shear rate in the laminar flow region proximal and distal to the stenoses was 420 sec-1. The surface of the stenosis was purified collagen type III fibrils that were exposed to flowing nonanticoagulated human blood drawn directly from an antecubital vein by a pump placed distally to the perfusion chamber. The resulting blood-collagen interactions were quantified by light microscopy by using a morphometric image analysis technique. Under all conditions studied, platelet thrombus formation at the "apex" was extensive.(ABSTRACT TRUNCATED AT 250 WORDS)
R. S. Rosenson, C. C. Tangney, J. M. Hafner
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1928-1932; https://doi.org/10.1161/01.atv.14.12.1928

Abstract:
Prospective population studies have established that fibrinogen is an independent predictor for ischemic heart disease and stroke. These study conclusions have prompted recommendations that fibrinogen determinations be included in the cardiovascular risk profile. The routine availability of fibrinogen measurements may result in widespread screening prior to establishing the validity of a single fibrinogen level as an accurate descriptor for individual subjects. The objectives of this study were to describe the methodological and intraindividual components of variability in fibrinogen measurements determined by using the Clauss method; to establish the usefulness of a single fibrinogen measurement on risk stratification and retest reproducibility; and to determine the influence of intraindividual fibrinogen variability on sample size estimates. Fibrinogen levels were measured by a modification of the Clauss method. Three cohorts of apparently healthy, nonsmoking volunteers were recruited. The single-day intra-individual component of fibrinogen variability was determined in 39 subjects. For the 5-day intraindividual component of fibrinogen variability, 32 subjects were recruited, and in the 6-week intraindividual study, 28 subjects were included. The coefficient of variation for the methodological component of fibrinogen variability was 5.8% as determined from batch analyses, but the intraindividual coefficient of variation for replicate measures on a single day was 10.7%. The 5-day intraindividual coefficient of variation was 14.2%, and for the 6-week period it was 17.8%. Based on the 6-week data, an average of four fibrinogen measures is required to reduce misclassification error to less than 10%. Sample size estimates were made based on predetermined levels of statistical power and the 6-week intraindividual and interindividual variability estimates.(ABSTRACT TRUNCATED AT 250 WORDS)
J D Bagdade, F L Dunn, R H Eckel, M C Ritter
Arteriosclerosis and Thrombosis: A Journal of Vascular Biology, Volume 14, pp 1933-1939; https://doi.org/10.1161/01.atv.14.12.1933

Abstract:
Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (CET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA1c IDDM, 6.9 +/- 1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P < .001) and both systemic insulin levels and LPL specific activity were increased (P < .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22 +/- 6.5 versus IP, 2.77 +/- 2.4 microU/mL; mean +/- SD; P < .025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL2) cholesterol, HDL3 cholesterol, cholesteryl ester transfer protein mass, and glycemic control (HbA1c, 6.3 +/- 0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET.(ABSTRACT TRUNCATED AT 250 WORDS)
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