bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of candidate autocrine and paracrine mediators on growth responses in isolated rat arteries.
Authors: Schiffers P M , Fazzi G E , van Ingen Schenau D , De Mey J G
Published: June 2011

We evaluated the effects of mediators that can be produced by smooth muscle and endothelial cells on growth responses in isolated arteries. Segments of carotid and renal arteries, denuded of endothelium, were isolated from adult rats and studied during tissue culture in the presence of indomethacin. Three days of culture in the presence of serum stimulated DNA synthesis in the media. During long-term culture new layers of cells developed at the borders of the arterial segments. Medial DNA synthesis depended less on serum than extramedial cell proliferation. During moderate stimulation, basic fibroblast growth factor and endothelin-1 enhanced and interleukin-1 and transforming growth factor-beta reduced medial DNA synthesis, whereas insulin-like growth factor-1, platelet-derived growth factor AA, platelet-derived growth factor BB, and angiotensin II were without effect. Of these factors, only endothelin-1 stimulated extramedial cell proliferation. In addition, serum-stimulated but not basic fibroblast growth factor-stimulated medial DNA synthesis was less marked in arteries that had not been denuded of endothelium than in ee-endothelialized arteries. Differences between preparations with and without endothelium persisted in the absence of L-arginine and in the presence of an inhibitor of nitric oxide synthase. These observations confirmed that DNA synthesis in the arterial media and extramedial cell proliferation are influenced by different factors. They further indicated that endothelial modulation of medial DNA synthesis does not seem to involved endothelium-derived prostaglandins, nitric oxide, or interleukin-1 and that it can be blunted by basic fibroblast growth factor.
Impact of myristic acid versus palmitic acid on serum lipid and lipoprotein levels in healthy women and men.
Authors: Zock P L , de Vries J H , Katan M B
Published: June 2011

The cholesterol-raising effect of dietary saturated fatty acids is largely accounted for by lauric, myristic, and palmitic acids. Dairy fat is a major source of myristic acid, and palm oil is especially rich in palmitic acid. Myristic acid is suspected of being much more cholesterolemic than palmitic acid, but direct comparisons have been lacking. We therefore fed 36 women and 23 men three diets that differed from each other in palmitic, oleic, and myristic acid content by about 10% of total energy. We used palm oil, high-oleic acid sunflower oil, and a specially produced high-myristic acid fat to achieve these differences. Each diet was consumed for 3 weeks in random order. Mean serum cholesterol was 4.53 mmol/L on the high-oleic acid diet, 4.96 mmol/L on the palmitic acid diet, and 5.19 mmol/L on the myristic acid diet (P < .0001 for all comparisons). Myristic acid raised low-density lipoprotein (LDL) cholesterol by 0.11 mmol/L, high-density lipoprotein (HDL) cholesterol by 0.12 mmol/L, and apolipoprotein (apo) A-I by 7.2 mg/dL relative to palmitic acid; increases relative to oleic acid were 0.50 mmol/L for LDL cholesterol, 0.15 mmol/L for HDL cholesterol, 6.0 mg/dL for apoB, and 8.9 mg/dL for apoA-I (P < .01 for all comparisons). The HDL cholesterol and apoA-I levels on the palmitic and oleic acid diets were the same. None of the responses differed significantly between woman and men. Myristic acid and palmitic acid both caused high LDL cholesterol and apoB levels and low HDL to LDL ratios.(ABSTRACT TRUNCATED AT 250 WORDS)
ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum.
Authors: Palinski W , Ord V A , Plump A S , Breslow J L , Steinberg D , Witztum J L
Published: June 2011

Apolipoprotein (apo) E-deficient transgenic mice develop marked hyperlipidemia and progressive atherosclerotic lesions. To explore whether oxidative modification of lipoproteins is involved in atherogenesis in this murine model, we performed extensive immunocytochemical studies. Atherosclerotic lesions ranging from early fatty streaks to very advanced plaques were examined from the aortic valve region and the thoracic and abdominal aorta. Using guinea pig antisera against malondialdehyde (MDA)-lysine and 4-hydroxynonenal-lysine, two epitopes generated during the oxidative modification of low-density lipoprotein (LDL), we demonstrated the presence of these "oxidation-specific epitopes" in atherosclerotic lesions. In early lesions, oxidation-specific epitopes were found predominantly in macrophage-rich areas, whereas diffuse extracellular staining predominated in necrotic areas of advanced lesions. We have previously shown that autoantibodies against MDA-lysine are present in the circulation of humans and rabbits and that the immunoglobulin fraction extracted from their lesions contains autoantibodies against several "oxidation-specific" epitopes. Sera from apoE-deficient mice also contained circulating autoantibodies to MDA-lysine, and both early and advanced lesions were rich in murine immunoglobulins. Titers of serum autoantibodies were significantly higher in apoE-deficient mice than in C57BL/6 mice. Autoantibodies in murine plasma recognized MDA-lysine epitopes in atherosclerotic lesions of rabbits, and the immunostaining was competitively inhibited by excess human MDA-LDL. Similar findings were obtained by competitive radioimmunoassay. Finally, a morphometric technique was developed and tested in these mice that allows a quantitative assessment of aortic atherosclerosis. These findings suggest that in apoE-deficient mice, lipoprotein oxidation is involved in atherogenesis and that these transgenic mice constitute an appropriate model with which to study the antiatherogenic effect of antioxidant intervention.
The association of hypotestosteronemia with coronary artery disease in men.
Authors: Phillips G B , Pinkernell B H , Jing T Y
Published: June 2011

Hyperestrogenemia and hypotestosteronemia have been observed in association with myocardial infarction (MI) and its risk factors. To determine whether these abnormalities may be prospective for MI, estradiol and testosterone, as well as risk factors for MI, were measured in 55 men undergoing angiography who had not previously had an MI. Testosterone (r = -.36, P = .008) and free testosterone (r = -.49, P < .001) correlated negatively with the degree of coronary artery disease after controlling for age and body mass index. When the patient group was successively reduced to a final study group of 34 men by excluding the patients with other major disorders, the testosterone and free testosterone correlations persisted (r = -.43, P < .02 and r = -.62, P < .001, respectively). Neither estradiol nor the risk factors, except for high-density lipoprotein cholesterol, correlated with the degree of coronary artery disease in the final group. Testosterone correlated negatively with the risk factors fibrinogen, plasminogen activator inhibitor-1, and insulin and positively with high-density lipoprotein cholesterol. The correlations found in this study between testosterone and the degree of coronary artery disease and between testosterone and other risk factors for MI raise the possibility that in men hypotestosteronemia may be a risk factor for coronary atherosclerosis.
Human HDL cholesterol levels are determined by apoA-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Effects of gender, hepatic and lipoprotein lipases, triglyceride and insulin levels, and body fat distribution.
Authors: Brinton E A , Eisenberg S , Breslow J L
Published: June 2011

High-density lipoprotein (HDL) cholesterol (HDL-C) levels are a strong inverse predictor of atherosclerosis risk, but the physiological determinants of HDL-C levels are poorly understood. We selected 57 human subjects (30 women and 27 men) with a broad range of HDL-C levels and performed turnover studies of apolipoprotein (apo)A-I and apoA-II, the two major apolipoproteins of HDL, to measure the fractional catabolic rate (FCR) and production or transport rate (TR) of these proteins. We also measured several other parameters known to correlate with HDL-C levels to test for their interrelations and to postulate mechanisms of regulation of HDL-C levels. As expected, the women had higher levels of HDL-C (56.7 +/- 21.4 versus 45.1 +/- 16.3 mg/dL, mean +/- SD; P = .03) and apoA-I (147 +/- 32 versus 126 +/- 29 mg/dL, P = .01) than men and did not differ in apoA-II levels (34.5 +/- 7.4 versus 33.3 +/- 7.5 mg/dL, P > .2). The FCR of apoA-I tended to be lower in the women (0.248 +/- 0.077 versus 0.277 +/- 0.069 pools/d, P = .1), although the difference was not statistically significant. The FCR of apoA-II was also lower (0.184 +/- 0.043 versus 0.216 +/- 0.056 pools/d, P = .02). In contrast, the apoA-I TR was equal in women and men (12.0 +/- 1.6 versus 12.1 +/- 2.8 mg/kg per day, P > .2), and there was a trend toward lower apoA-II TR in women (2.19 +/- .62 versus 2.61 +/- 1.06 mg/kg per day, P = .07). Linear regression analysis revealed a strong inverse correlation between HDL-C levels and the FCRs of apoA-I and apoA-II (r = -.81 and -.76, respectively; P < .0001 for both). In contrast, there was little or no association between HDL-C and the TRs of apoA-I and apoA-II (r = .06 and -.35, P = not significant and .01, respectively). In stepwise multiple linear regression analysis, apoA-I FCR alone accounted for 66% of the variability in HDL-C; two other variables accounted for an additional 7%. Due to the importance of apoA-I FCR, its determinants were sought among the remaining variables.(ABSTRACT TRUNCATED AT 400 WORDS)
Cell proliferation after balloon injury of iliac arteries in the cholesterol-fed New Zealand White rabbit.
Authors: Stadius M L , Gown A M , Kernoff R , Collins C L
Published: June 2011

Acute mechanical injury of an artery results in neointimal hyperplasia that is due at least in part to cell proliferation within the vessel wall. The purpose of this study was to quantify cell proliferation activity in the iliac artery of New Zealand White rabbits after balloon injury and cholesterol feeding. Retrograde pullback balloon injury of iliac arteries was performed, and the animals were then fed a 2% cholesterol diet. At intervals from day 1 through day 35 postinjury, iliac arteries were obtained for histological analysis. Intimal and medial areas were measured morphometrically. Total number of cells within the intima and media was counted. Smooth muscle cell-predominant or macrophage-predominant regions of the intima and media were identified using HHF-35 and RAM-11 immunocytochemical markers, respectively. Number of cells in the proliferative phase of the cell cycle was measured by using the proliferating cell nuclear antigen and bromodeoxyuridine techniques. Thirty-one arteries from 16 rabbits were available for analysis. Total number of cells and number of cells per square millimeter within the media did not change significantly from day 1 through day 35 postinjury. Total number of cells within the intima increased significantly, but the number of cells per square millimeter of intima decreased significantly during the same time period. Proliferative activity was identified in the media between days 3 and 35 with peak activity at day 3 postinjury. Proliferative activity in the intima was present in all specimens from day 8 through day 35. Proliferative activity was present in both HHF-35- and RAM-11-predominant regions of the intima.(ABSTRACT TRUNCATED AT 250 WORDS)
Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell formation.
Authors: Geng Y , Kodama T , Hansson G K
Published: June 2011

Scavenger receptors mediate binding and uptake of chemically modified lipoproteins. cDNA cloning of the human macrophage scavenger receptor (MSR) reveals the presence of two mRNA species, the type I and II isoforms, which are generated by 3' alternative splicing of a single MSR gene and translated into two proteins with different C-terminal domains. We studied MSR isoform expression during the differentiation from circulating monocytes to adherent macrophages and subsequently to lipid-laden foam cells. Differentiation from monocyte to macrophage was associated with a prominent increase in MSR expression on the mRNA, protein, and cell surface levels, leading to an increased uptake of acetylated low-density lipoprotein (LDL). Further analyses of mRNA and proteins revealed that both MSR isoforms were present in low and approximately equal amounts on the surface of CD14+ peripheral blood monocytes; these cells had approximately similar levels of type I and type II MSR mRNA species. During differentiation to macrophages, there was a rapid, selective increase in type I MSR mRNA, with type II mRNA being expressed at approximately the same level as in the monocyte. This, in turn, resulted in an increase in type I MSR protein on the cell surface during differentiation from monocyte to macrophage. Type I MSR mRNA also dominated during the transformation of macrophages to foam cells in the presence of acetylated LDL. These findings suggest that the increased uptake of modified LDL during differentiation from monocyte to macrophage is accomplished by a selective upregulation of type I MSRs on the mRNA level. The increased expression of type I MSRs may be important for foam cell formation.
Effects of increasing dietary polyunsaturated fatty acids within the guidelines of the AHA step 1 diet on plasma lipid and lipoprotein levels in normal males.
Authors: Ginsberg H N , Karmally W , Barr S L , Johnson C , Holleran S , Ramakrishnan R
Published: June 2011

We attempted to ascertain the effects of polyunsaturated fatty acids by conducting two studies in normal young men, in which monounsaturated fats were replaced by polyunsaturated fats within the guidelines of the American Heart Association step 1 diet. Study A employed a randomized parallel design in which subjects first consumed an average American diet (AAD) containing 37% of calories as fat (saturated fat, 16% calories; monounsaturated fat, 14% calories; and polyunsaturated fat, 7% calories). After 3 weeks, one third of the subjects continued with the AAD, one third switched to a step 1 diet in which total fat calories were reduced to 30% by replacing saturated fat with carbohydrate, and one third switched to a polyunsaturated fat-enriched (Poly) diet with the same 30% fat calories and a reduction of monounsaturated fat from 14% to 8% and an increase of polyunsaturated fat from 7% to 13% of calories. The randomized period lasted 6 weeks. Total and low-density lipoprotein (LDL) cholesterol levels on the step 1 and Poly diets were reduced compared with levels on the AAD (P < .001). Total and LDL cholesterol did not differ between the step 1 and Poly diets, although comparison between the two diets is limited by the small study groups. Serum apolipoprotein (apo) B levels fell on the Poly diet compared with the AAD. Total high-density lipoprotein (HDL), HDL2, and HDL3 cholesterol levels were not significantly affected by the diets. Postprandial lipid and lipoprotein concentrations did not significantly differ either. In study B, a randomized crossover design was used in which all subjects ate the step 1 and Poly diets for 5 weeks each with a 4-day break between diets. In the eight subjects studied, the values for fasting plasma total, LDL, and HDL cholesterol; triglycerides; apoB; and apoA-I were essentially identical at the end of each diet period. Postprandial triglyceride areas obtained after ingestion of a large, standard fat load were also the same. Finally, LDL apoB and HDL apoA-I turnovers were unaffected by replacement of monounsaturates with polyunsaturates. In summary our results indicate that modest exchanges of monounsaturated for polyunsaturated fats do not significantly affect LDL or HDL levels or metabolism, which supports the view that reducing saturated fats is the key to lowering total and LDL cholesterol.
L-arginine improves endothelium-dependent vasorelaxation and reduces intimal hyperplasia after balloon angioplasty.
Authors: Tarry W C , Makhoul R G
Published: June 2011

Reductions in nitric oxide (NO) activity persist after arterial intimal injury and may be a factor in the development of intimal hyperplasia. NO inhibits in vitro platelet aggregation, leukocyte adhesion, and smooth muscle cell growth, all of which are key components in the process of intimal hyperplasia. We hypothesized that long-term supplementation with L-arginine, the precursor of NO, would increase NO production and thereby improve endothelium-dependent vasorelaxation and simultaneously reduce intimal hyperplasia. Twenty-six New Zealand White male rabbits were fed standard rabbit chow either with or without 2.25% L-arginine in their drinking water for 3 weeks. Then the animals underwent unilateral iliac artery angioplasty and were continued on their respective diets. Four weeks after angioplasty, the iliac arteries were harvested for functional and morphometric studies. The iliac arteries from several animals from each group were processed for study by electron microscopy. Maximal endothelium-dependent vasorelaxation in injured arteries was significantly greater in L-arginine-supplemented animals (mean +/- SEM, 71.8 +/- 4.1%; n = 6) than controls (51.4 +/- 4.0%, n = 7; P < .05). Furthermore, the intimal area in injured arteries was significantly reduced in L-arginine-supplemented animals (0.22 +/- 0.03 mm2, n = 5) compared with controls (0.34 +/- 0.03 mm2, n = 6; P < .05). These data suggest that L-arginine supplementation enhances NO production at sites of vascular healing and may reduce intimal hyperplasia.
Mast cells of two types differing in neutral protease composition in the human aortic intima. Demonstration of tryptase- and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas.
Authors: Kaartinen M , Penttilä A , Kovanen P T
Published: June 2011

Biochemical studies in vitro have demonstrated that stimulated mast cells induce macrophage foam cell formation through the synergistic action of mast cell granule neutral proteases and proteoglycans. To determine the presence and number of mast cells in human arterial intima, the site of atherogenesis, specimens of normal and atherosclerotic human aortic intima from 35 autopsies of persons ranging from 13 to 67 years old were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase. All mast cells present were found to contain tryptase, and an average of 40% contained chymase as well. In sections of normal intimas, fatty streaks, and atheromas, the mast cells had average densities of 15/mm2, 15/mm2, and 3/mm2, respectively. In contrast to the normal intimas and fatty streaks, however, the atheromas had mast cells distributed unevenly in a typical pattern: 8/mm2 in the shoulder region, 1/mm2 in the fibrous cap, and none in the core region. In normal intimas, fatty streaks, and the shoulder region of atheromas, the mast cells amounted to 3% of all nucleated cells. The ratios of mast cells to T lymphocytes and to macrophages, respectively, were 2:1 and 1:4 in normal intimas, 1:3 and 1:10 in fatty streaks, and 1:5 and 1:20 in the shoulder region of atheromas. Thus, among the blood-borne cells in the human aortic intima, mast cells compose a significant cell population, and in terms of their protease content, these intimal mast cells are heterogeneous.(ABSTRACT TRUNCATED AT 250 WORDS)
Protein tyrosine kinase inhibitors inhibit chemotaxis of vascular smooth muscle cells.
Authors: Shimokado K , Yokota T , Umezawa K , Sasaguri T , Ogata J
Published: June 2011

The effects of protein tyrosine kinase inhibitors on platelet-derived growth factor (PDGF)-induced chemotaxis in cultured rat aortic smooth muscle cells (SMCs) were investigated to elucidate the role of tyrosine phosphorylation in the chemotaxis of vascular SMCs. Two tyrosine kinase inhibitors, methyl 2,5-dihydroxycinnamate and genistein, inhibited PDGF-induced chemotaxis, the IC50 being 5 and 150 mumol/L, respectively. Methyl cinnamate and genistein partly inhibited the adhesion of SMC to collagen-coated dishes. A chemotaxis assay using double-well culture dishes revealed that both agents also inhibited cell migration after adhesion. H-7, a C kinase inhibitor, did not inhibit either chemotaxis or SMC adhesion at 100 mumol/L. Western blot analysis using anti-phosphotyrosine revealed that the tyrosine kinase inhibitors inhibited the tyrosine phosphorylation of at least two proteins of molecular weight 85 and 95 kD under our experimental conditions. An immunocytochemical study revealed that these inhibitors eliminated tyrosine phosphorylation along the cell margins; these agents also inhibited the reorganization of microtubules and stress fibers, both of which are involved in directional cell locomotion. These findings suggest that tyrosine kinases may play an important role in SMC chemotaxis.
Interleukin-1 upregulates decorin production by arterial smooth muscle cells.
Authors: Edwards I J , Xu H , Wright M J , Wagner W D
Published: June 2011

An increase in dermatan sulfate-proteoglycan (DSPG) production occurs in cultured aortic smooth muscle cells exposed to macrophage-conditioned media, an effect that is abrogated by an antibody to interleukin-1 (IL-1). To determine which DSPG gene was regulated, cultured arterial smooth muscle cells from monkeys (Macaca fascicularis) were treated with 0 to 500 pg/mL human recombinant IL-1 alpha or IL-1 beta in the presence of [35S]sulfate and [3H]serine. Proteoglycans were isolated from the culture media and purified by selective precipitation and chromatography. Both recombinant IL-1 alpha and IL-1 beta caused a dose-response increase in DSPG production. Northern blot analysis of mRNA isolated from the cells identified 1.6-kb and 2.6-kb transcripts homologous to the cDNA encoding human decorin and biglycan, respectively. IL-1 treatment resulted in increases in the steady-state level of decorin mRNA as high as fourfold to sixfold at 500 pg/mL recombinant IL-beta. By contrast, mRNA for biglycan was unchanged. Western blotting confirmed a specific enhancement of the 45-kD decorin core protein. These data indicate that IL-1 has differential effects on the two DSPG genes and suggest that macrophages may be capable of modifying the extracellular matrix of the artery wall by enhancing smooth muscle cell decorin production.
Effect of notoginsenoside R1 on the synthesis of tissue-type plasminogen activator and plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells.
Authors: Zhang W , Wojta J , Binder B R
Published: June 2011

Among other Chinese herb drugs, Panax notoginseng is used to treat cardiovascular diseases. To elucidate any possible effects of this drug on the hemostatic system in vitro, we analyzed the influence of one of its major active constituents on fibrinolytic parameters of cultured human umbilical vein endothelial cells (HUVECs). When confluent cultures of HUVECs (passages 2 to 3) were conditioned with purified notoginsenoside R1 (NR1), a dose- (0.01 to 100 micrograms NR1/mL) and time-dependent increase in tissue-type plasminogen activator (TPA) synthesis was observed, which was significant from 0.1 microgram NR1/mL and from 6 hours of incubation with 100 micrograms NR1/mL on. TPA antigen increased from 3.9 +/- 0.2 ng per 10(5) cells per 24 hours to 8.0 +/- 0.5 ng per 10(5) cells per 24 hours on addition of 100 micrograms NR1/mL. In contrast, no change in urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1) antigen synthesis was seen. There was also no effect of NR1 on PAI-1 deposition in the extracellular matrix. As judged from fibrin autography and reverse fibrin autography, TPA activity and TPA-PAI-1 complexes reached a maximal stimulation of more than threefold and twofold, respectively, at a concentration of 100 micrograms NR1/mL in conditioned media. On the contrary, NR1 induced a more than fivefold decrease in PAI-1 activity at the same concentration of NR1 in conditioned media. On Northern blot analysis of RNA obtained from NR1-stimulated and control HUVECs, NR1 induced a significant increase in TPA mRNA (192% of control value at 100 micrograms NR1/mL) while PAI-1 mRNA remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of DNA changes in the LPL gene in patients with familial combined hyperlipidemia.
Authors: Gagné E , Genest J , Zhang H , Clarke L A , Hayden M R
Published: June 2011

Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by an increase in cholesterol and/or triglyceride levels in multiple individuals of the same family. Prior reports document a decreased activity of lipoprotein lipase (LPL) in FCHL, and studies of the role of LPL in the remodeling of nascent lipoproteins suggest that disturbances in LPL function could underlie FCHL. We studied the LPL gene in 31 unrelated individuals with FCHL. A total of 25 DNA changes (13 "silent" substitutions and 12 DNA changes resulting in amino acid substitutions) were detected in 16 patients. Three new exonic polymorphisms as well as a previously described Ser447-->stop and an Asp9-->Asn substitution were seen with similar frequency on control and FCHL chromosomes. Two novel DNA changes resulting in an Asp21-->Val and an His44-->Tyr substitution were seen in only two FCHL individuals. In vitro studies showed no effect of these mutations on LPL catalytic activity. LPL mutations impairing catalytic activity did not represent a significant factor leading to FCHL in this population. Variations in any portion of the coding region of the LPL gene affecting other functions besides catalysis are not a frequent cause of FCHL.
Response to HMG CoA reductase inhibitors in heterozygous familial hypercholesterolemia due to the 10-kb deletion ("French Canadian mutation") of the LDL receptor gene.
Authors: Karayan L , Qiu S , Betard C , Dufour R , Roederer G , Minnich A , Davignon J , Genest J
Published: June 2011

The 10-kb deletion ("French Canadian mutation") of the low-density lipoprotein (LDL) receptor gene is the most common mutation causing familial hypercholesterolemia among subjects of French Canadian descent. In affected subjects, it results in a null allele of the LDL receptor gene and provides a unique opportunity to examine single-allele regulation of this gene in humans. We sought to ascertain the response of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in subjects with the French Canadian mutation of the LDL receptor gene and to correlate this response with biochemical variables and the haplotype of the nondeletion LDL receptor allele. The prevalence of non-responders to high doses of HMG CoA reductase inhibitors (defined as < 15% decrease in LDL cholesterol [LDL-C] from baseline values after dietary intervention) was ascertained in 105 patients heterozygous for the 10-kb deletion after excluding first-degree relatives and those on combined lipid-lowering therapy or other lipid-lowering agents. Lipoprotein cholesterol levels were examined after a diet period (30% calories as fat) and after receiving HMG CoA reductase inhibitors as mono-therapy for a minimum of 3 months. The mean reduction in total cholesterol was 45 +/- 23%, in LDL-C 33 +/- 15%, and in triglycerides 32 +/- 49% (all P < .005). There was a slight increase in high-density lipoprotein cholesterol of 8.5 +/- 18% (P > .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor-1 activity.
Authors: Mykkänen L , Rönnemaa T , Marniemi J , Haffner S M , Bergman R , Laakso M
Published: June 2011

It recently has been hypothesized that increased plasma plasminogen activator inhibitor-1 (PAI-1) activity could be a possible link between insulin resistance and coronary heart disease. However, it is not known whether insulin sensitivity per se is a determinant of plasma PAI-1 activity or whether other intermediates could explain this association. We investigated the relationship between plasma PAI-1 activity and insulin sensitivity, obesity, distribution of body fat, blood pressure, plasma insulin concentration, and serum lipid levels in normoglycemic men (n = 61) and women (n = 77) 53 to 61 years old who participated in a previous population-based study. Insulin sensitivity was estimated by the minimal model from a frequently sampled intravenous glucose tolerance test. In univariate analyses, PAI-1 correlated positively with body mass index, waist-to-hip ratio (WHR), fasting and 2-hour insulin levels, and triglyceride level in both men and women. Furthermore, in women PAI-1 correlated inversely with high-density lipoprotein (HDL) cholesterol level. There was an inverse relationship between PAI-1 and insulin sensitivity (r = -.39, P < .01 in men; r = -.38, P < .001 in women). In multivariate analyses in men, insulin sensitivity failed to show any significant association with PAI-1. In contrast, triglyceride level and body mass index were independently associated with PAI-1. Also in women, insulin sensitivity was not independently associated with PAI-1. In women, WHR and HDL cholesterol concentration or WHR and 2-hour insulin concentration were independently related to PAI-1.(ABSTRACT TRUNCATED AT 250 WORDS)
Early changes of the arterial carotid wall in uncomplicated primary hypertensive patients. Study by ultrasound high-resolution B-mode imaging.
Authors: Ferrara L A , Mancini M , Celentano A , Galderisi M , Iannuzzi R , Marotta T , Gaeta I
Published: June 2011

Arterial hypertension is frequently responsible for arteriosclerotic damage in the carotid region. Nevertheless, there is as yet no general agreement that hypertension is correlated with lesions detected by noninvasive means in the carotid arteries. We studied, by noninvasive echotomographic technique, 70 uncomplicated primary hypertensive individuals without clinically evident end-organ complications and 30 normotensive matched control subjects to detect early lesions of carotid arteries. The presence of other cardiovascular risk factors was assessed, and heart structure and function were studied by echocardiography. Although hypertensive individuals were comparable to control subjects for other risk factors, they showed a marked increase in the thickness of the intimal-medial complex of the carotid wall (0.71 +/- 0.4 versus 0.56 +/- 0.2 mm, P < .001 in the right carotid and 0.83 +/- 0.3 versus 0.58 +/- 0.2, P < .003 in the left), in left ventricular mass (203 +/- 52 versus 176 +/- 37 g, P < .05), and in the prevalence of definite plaques of the carotid wall, both monolaterally and bilaterally (P < .003 by chi 2 test). Among the different factors contributing to the increase in thickness of the carotid artery wall, standing blood pressure, serum triglycerides, and age were found to be the best predictors (they accounted for about 16% of the variability, P < .005). These results indicate that carotid arteries of hypertensive individuals undergo degenerative changes, just as shown for hypercholesterolemic and diabetic patients in other studies. This supports the use of B-mode ultrasound imaging to detect early involvement of the carotid region before the appearance of any end-organ damage of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Ultrasound evaluation of atherosclerotic manifestations in the carotid artery in high-risk hypertensive patients. Risk Intervention Study (RIS) Group.
Authors: Suurküla M , Agewall S , Fagerberg B , Wendelhag I , Widgren B , Wikstrand J
Published: June 2011

The aim of this study was to evaluate whether high-risk hypertensive patients (n = 137) had larger far-wall common carotid artery intima-media thickness than a control group (n = 37) and to study whether intima-media thickness was related to other signs of atherosclerotic disease. The results showed that intima-media thickness was significantly larger in the hypertension group than in the control group. Lumen diameter and mean cross-sectional area of the intima-media complex were larger both for hypertensive patients with a positive history of manifest clinical cardiovascular disease and for hypertensive patients with no such history than in the control group. There was a significant relationship between far-wall common carotid artery intima-media thickness and plaque status (visual scoring, no, small, moderate/large) in the carotid artery region. In univariate analyses, low diastolic blood pressure and high pulse pressure were both significantly related to plaque status. In multivariate analyses, pulse pressure was significantly and independently related both to common carotid artery intima-media thickness and to plaque status in the carotid artery region. In multivariate analyses, there was also an independent relationship between age and common carotid artery intima-media thickness, between smoking status and plaque status, and between a positive history of manifest clinical cardiovascular disease and plaque status. In conclusion, common carotid artery intima-media thickness and lumen diameter were increased in elderly high-risk hypertensive patients, in whom more than one third of the patients also had a moderate to large plaque in the carotid artery region.(ABSTRACT TRUNCATED AT 250 WORDS)
Macrophage foam cell lipoprotein(a)/apoprotein(a) receptor. Cell-surface localization, dependence of induction on new protein synthesis, and ligand specificity.
Authors: Keesler G A , Li Y , Skiba P J , Fless G M , Tabas I
Published: June 2011

Understanding the interaction of the atherogenic lipoprotein, lipoprotein(a) [Lp(a)], with macrophages may provide important insight into the physiology and pathophysiology of this lipoprotein. We have recently shown that cholesterol loading of macrophages, such as occurs in atheroma foam cells, leads to marked upregulation of a novel receptor activity for native Lp(a) and its plasminogen-like protein component, apoprotein(a) [apo(a)]. We show here that the Lp(a)/apo(a) receptor activity on cholesterol-loaded macrophages is trypsin sensitive, indicating that a cell-surface protein is involved and that the upregulation by cholesterol loading requires new protein synthesis. Ligand studies revealed that the foam cell receptor activity recognizes Lp(a) containing both small and large isoforms of apo(a) as well as rhesus monkey Lp(a), which contains an inactive kringle-4(37) (K4(37) lysine-binding domain. Elastase degradation products of plasminogen did not compete for 125I-labeled recombinant apo(a) [125I-r-apo(a)] internalization and degradation by foam cells, indicating that the K4(37) sequence, as well as the K5 and "protease" domains of apo(a), are not sufficient for receptor interaction. Consistent with these data, the degradation of 125I-r-apo(a) was completely blocked by an anti-Lp(a) polyclonal antibody that does not cross-react with plasminogen. Furthermore, the multiple sialic residues of apo(a) are also not involved in receptor interaction, since desialylated r-apo(a) interacted with foam cells as well as native r-apo(a). In contrast, reduced and denatured r-apo(a) was degraded by foam cells only slightly better than by control cells [28% increased degradation by foam cells versus 450% for native r-apo(a)], suggesting that the upregulated receptor activity recognizes certain secondary and tertiary structural features of apo(a).(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclosporin A has divergent effects on plasma LDL cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] levels in renal transplant recipients. Evidence for renal involvement in the maintenance of LDL-C and the elevation of Lp(a) concentrations in hemodialysis patients.
Authors: Azrolan N , Brown C D , Thomas L , Hayek T , Zhao Z H , Roberts K G , Scheiner C , Friedman E A
Published: June 2011

Cardiovascular disease is the major cause of mortality in renal transplant recipients. Plasma levels of low-density lipoprotein cholesterol (LDL-C) are often elevated following renal transplantation, and the immunosuppressant cyclosporin A has been implicated as a predisposing factor for posttransplantation hyperlipidemia. Lipoprotein(a) [Lp(a)] is an LDL-like lipoprotein particle; elevated levels of Lp(a) provide an independent and significant risk factor for cardiovascular disease. Plasma concentrations of Lp(a) vary greatly among individuals, and the mechanisms that govern changes in their levels in transplant patients are unknown. The effect(s) of cyclosporin A on Lp(a) was studied in two groups of renal transplantation patients. In group I plasma lipoproteins including Lp(a) were measured before and after successful renal transplantation; this group received both prednisone and cyclosporin A for immunosuppression. Group II patients were studied after renal transplantation and received prednisone alone for immunosuppression. Following surgery, group I patients demonstrated increased plasma concentrations of LDL-C (mean +/- SEM range, 111 +/- 6 to 142 +/- 17 mg/dL; P < .005). In contrast, plasma Lp(a) levels for this group were markedly decreased after renal transplantation (median, 34.3 to 19.7 mg/dL). Patients not treated with cyclosporin A (group II) exhibited mean LDL-C and median Lp(a) levels (118 +/- 42 and 33.1 mg/dL, respectively) that were remarkably similar to those observed before renal transplantation (group I). These data confirm that hyperlipidemia following renal transplantation is associated with cyclosporin A therapy and show that this drug has opposing effects on plasma Lp(a) and LDL-C accumulations.(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoprotein(a) phenotype-associated decrease in lipoprotein(a) plasma concentrations after renal transplantation.
Authors: Kronenberg F , König P , Lhotta K , Ofner D , Sandholzer C , Margreiter R , Dosch E , Utermann G , Dieplinger H
Published: June 2011

High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. In the general population, Lp(a) levels are primarily determined by allelic variation at the apolipoprotein(a) [apo(a)] gene locus. Apo(a) isoforms of various sizes are associated with different Lp(a) concentrations. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by the size variation at the apo(a) gene locus. To further investigate the origin of the elevated Lp(a) plasma concentrations, we examined Lp(a) concentrations and apo(a) phenotypes in 154 ESRD patients undergoing renal transplantation. In a prospective longitudinal study we observed a rapid normalization of Lp(a) levels from an average concentration of 25.9 +/- 28.7 mg/dL before to 17.9 +/- 25.5 mg/dL 3 weeks after renal transplantation (P < .0001). Only patients with high-molecular-weight phenotypes had a significant decrease in Lp(a) plasma concentrations. This study demonstrates the nongenetic origin of elevated Lp(a) concentrations in ESRD patients, which is obviously caused by the disease. It further confirms a phenotype-associated elevation of Lp(a) concentrations in ESRD.
Apolipoprotein(a) phenotypes predict the risk for carotid atherosclerosis in patients with end-stage renal disease.
Authors: Kronenberg F , Kathrein H , König P , Neyer U , Sturm W , Lhotta K , Gröchenig E , Utermann G , Dieplinger H
Published: June 2011

Several studies have demonstrated that atherosclerotic complications are the major cause of morbidity and mortality in hemodialysis patients. High lipoprotein(a) [Lp(a)] plasma concentrations are an independent risk factor for atherosclerosis. Patients with end-stage renal disease (ESRD) have elevated plasma concentrations of Lp(a), which are not explained by size variation at the apolipoprotein(a) [apo(a)] gene locus. The aim of our study was to investigate whether Lp(a) concentrations and/or apo(a) phenotypes are predictive of the degree of atherosclerosis in the extracranial carotid arteries in ESRD patients. Of 167 patients, 108 showed atherosclerotic plaques (65%). Univariate analysis showed that the plaque-affected group was significantly older and had a higher frequency of angina pectoris, previous myocardial infarction, or cerebrovascular accident. Furthermore, this group included significantly more patients with low-molecular-weight apo(a) isoforms (26.9% versus 8.5%, P < .005) and had significantly higher mean Lp(a) plasma concentrations (29.3 +/- 31.0 versus 19.7 +/- 25.7 mg/dL, P < .05). Lp(a) plasma concentration increased significantly with the number of affected arterial sites, from 19.7 mg/dL in patients without plaques to 40.1 mg/dL in patients with seven or eight affected sites. In patients with low-molecular-weight phenotypes, significantly more arterial sites were affected (3.62 versus 2.08, P < .001). Multivariate regression analysis showed that age, angina pectoris, and the apo(a) phenotype were the only significant predictors of the degree of atherosclerosis. We conclude that, besides age, the apo(a) phenotype is the best predictor of carotid atherosclerosis in ESRD patients and may be used for assessment of general atherosclerosis risk in this patient group.
Lipoprotein lipase is produced by cardiac myocytes rather than interstitial cells in human myocardium.
Authors: O'Brien K D , Ferguson M , Gordon D , Deeb S S , Chait A
Published: June 2011

Lipoprotein lipase (LPL) may play an important role in myocardial metabolism by releasing free fatty acids from triglycerides for oxidation by myocytes. However, studies in species other than humans have differed in their conclusions as to whether LPL is produced by cardiac myocytes or interstitial cells. The location and source of LPL in human myocardium were determined on formalin-fixed samples from 25 cardiomyopathy patients and seven control patients. LPL protein was detected immunohistochemically on cardiac myocytes, adipocytes, and endothelial cells, as well as on interstitial cells consisting of both vascular pericytes and smooth muscle cells. In all 32 patients, in situ hybridization localized LPL mRNA to cardiac myocytes and adipocytes, but LPL mRNA was not detected in interstitial cells. Quantitative in situ hybridization failed to reveal correlations between LPL mRNA levels and New York Heart Association functional class, left ventricular ejection fraction, or beta-adrenergic agonist therapy. Also, quantitative in situ hybridization demonstrated apparently linear loss of detectable myocardial mRNA after onset of ischemia, with a disappearance half-time of approximately 26 hours. In summary, LPL is produced primarily by cardiac myocytes rather than by interstitial cells in human myocardium. Furthermore, LPL protein is present on cells with and without detectable LPL mRNA, suggesting that LPL is translocated from sites of synthesis to sites of utilization.
Plasminogen activator inhibitor-1 released from activated platelets plays a key role in thrombolysis resistance. Studies with thrombi generated in the Chandler loop.
Authors: Stringer H A , van Swieten P , Heijnen H F , Sixma J J , Pannekoek H
Published: June 2011

To investigate the potential role of plasminogen activator inhibitor-1 (PAI-1), which is released from the alpha-granules of activated platelets, in thrombolysis resistance, we employed a model (the "Chandler loop") that mimics the formation of arterial thrombi in vivo and that can be manipulated in terms of rheological parameters and composition of blood cells. Light and electron microscopy revealed that the distribution of blood cells in Chandler thrombi is polarized, as it is in arterial thrombi, resulting in platelet-rich "white heads" and red blood cell-rich "red tails.". Resistance toward tissue-type plasminogen activator (TPA)-mediated thrombolysis parallels the presence of platelets that are fully activated in this system. We demonstrate that the PAI-1 released by the alpha-granules is preferentially retained within the thrombus and that the concentration of PAI-1 antigen is higher in the head than in the tail of the thrombus. The relative thrombolysis resistance of the heads of Chandler thrombi can be largely abolished by inclusion of an anti-PAI-1 monoclonal antibody that blocks that inhibitory activity of PAI-1 toward TPA. We propose that PAI-1, released from activated platelets, plays a key role in thrombolysis resistance and/or reocclusion after thrombolytic therapy. This is due to binding of PAI-1 to polymerized fibrin within the thrombus, followed by inhibition of TPA-mediated fibrinolysis.
Tissue-type plasminogen activator and its inhibitor in rat aorta. Effect of endotoxin.
Authors: Padró T , Quax P H , van den Hoogen C M , Roholl P , Verheijen J H , Emeis J J
Published: June 2011

Plasminogen activator (PA) and PA inhibitor (PAI) antigen, activity, and mRNA were analyzed in the three layers of rat aorta, and the effect of endotoxin on PA and PAI was studied. All PA activity in aorta was identified as tissue-type PA (TPA) activity; no urokinase-type PA was detected. In the tunica adventitia TPA activity, TPA antigen, and TPA mRNA were detected, whereas in the tunica media TPA antigen and TPA mRNA, but no TPA activity, were found. PAI activity was detected in the tunica media, explaining the absence of TPA activity in this layer. Removal of the endothelial cells had no effect on TPA antigen and PAI activity in intima-media preparations. Also, similar amounts of PAI-1 mRNA were found in intima-media preparations, irrespective of the presence or absence of the intima. Immunohistochemical staining showed that TPA immunoreactivity was present in all three layers of the aorta, whereas PAI-1 immunoreactivity was found in medial smooth muscle cells but not in endothelial cells. After endotoxin treatment, TPA activity was decreased in extracts of the total aorta and of the adventitia, although TPA antigen and TPA mRNA were unchanged. PAI-1 mRNA was strongly increased in the tunica adventitia and in the tunica media, as was PAI activity in the tunica media. Thus, endotoxin decreased TPA activity by increasing the synthesis of PAI-1; TPA was unaffected. Our observations in rat aorta differ from observations in mouse aorta and in rat carotid artery, and they caution against extrapolation from one tissue (or species) to another.
Collagen-Induced Thrombus Formation in Flowing Nonanticoagulated Human Blood From Habitual Smokers and Nonsmoking Patients With Severe Peripheral Atherosclerotic Disease
Authors: Roald Helge E. , Lyberg Torstein , Dedichen Henrik , Hamers Marjo , Kierulf Peter , Westvik Åse-Brit , Sakariassen Kjell S.
Published: June 2011

Abstract
The objective of the present study was to investigate collagen-induced platelet thrombus formation at arterial blood flow conditions in nonanticoagulated blood from habitual smokers and from nonsmoking patients with severe peripheral atherosclerotic disease. Collagen-induced thrombogenesis was elicited in native blood drawn directly from an antecubital vein over immobilized type III collagen fibrils coated on a coverslip positioned in a parallel-plate perfusion chamber. The wall shear rates at the collagen surface were comparable to those encountered in medium-sized (650 s
−1
) and moderately stenosed (2600 s
−1
) arteries. Thrombus formation in blood from habitual smokers after 10 hours of smoking abstinence appeared to be not different from thrombus formation in blood from healthy nonsmokers. However, immediately after a cigarette had been smoked, thrombus volume in blood from the same individuals was increased twofold at the highest shear rate (
P
<.05). Thus, the thrombotic response was temporarily upregulated after smoking. Thrombus formation in blood from nonsmoking patients with severe peripheral atherosclerotic disease was neither enhanced nor decreased but was within the range of the nonsmoking control subjects. However, fibrinopeptide A generation after 4 minutes of perfusion at 2600 s
−1
was higher in blood from the atherosclerotic patients (
P
<.05) and associated with a higher plasma fibrinogen level (
P
<.005). Thus, signs of changed platelet reactivity in flowing nonanticoagulated blood were encountered only in the habitual smokers immediately after they had smoked a cigarette.