ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

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 with3H-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.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Hypoalphalipoproteinemia (HA) is a common finding in patients with premature coronary artery disease. To characterize the common familial forms of HA, we studied 102 families of probands with premature coronary artery disease; 40 probands (39.2%) had HA. Of these, 25 had at least one first-degree relative affected with HA; 11 had familial hypertriglyceridemia with HA (FTgHA); 10 had familial combined hyperlipidemia (FCH); and 4 had familial HA (FHA) with no other lipoprotein abnormalities. In the remaining 15 families, no lipoprotein abnormalities were observed in first-degree relatives. We measured apolipoprotein (apo) A-I, B, C-IH, and E levels as well as lipoprotein particle (Lp) levels of LpA-I (containing apoA-I only), LpA-I:A-II (containing both apoA-I and A-II), LpB:E, and LpB:C-III. Compared with a reference group of healthy men (n = 103) and women (n = 106), probands with familial forms of HA had lower high-density lipoprotein cholesterol levels by selection criteria. Triglyceride levels were higher in FTgHA and FCH probands than in the reference group or FHA subjects. Despite selection of FTgHA and FCH by low-density lipoprotein (LDL) cholesterol, the latter was not significantly different between the three groups and the reference group. ApoA-I levels were decreased in FCH, FHA, and FTgHA probands, and LpA-I and LpA-I:A-II were lower in FHA and FTgHA probands. ApoB levels were significantly higher in all familial HA groups compared with the reference group, being highest in FCH individuals, but not significantly higher between FCH, FTgHA, or FHA probands. LpB:E levels were higher in the FCH and FTgHA groups than in the reference group. There were no significant differences between groups for apoE, apoC-III, and LpB:C-III. LDL particle size was smaller in all three forms of FHA, which, in combination with higher apoB levels, reflects an increased number of smaller, denser LDL particles. Affected children had, on average, higher apoB and LpB:E levels than nonaflected siblings. Our data suggest that common forms of FHA in subjects with coronary artery disease represent a spectrum of overlapping disorders characterized by an increase in apoB-containing lipoproteins, especially LpB:E particles, and smaller, denser LDL particles. When using appropriate ageand gender-adjusted cutpoints, approximately half the offspring (in young adulthood) appeared to be affected.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Immunohistochemical studies of human atherosclerotic lesions have demonstrated the occurrence of fibrin deposition and its degradation in the arterial wall. We studied fibrinogen, the generation of thrombin, and the degradation of fibrin in 40 patients with stable peripheral arterial occlusive disease of varying severity, as assessed by the ankle/brachial pressure index and duplex ultrasonography and/or angiography. Circulating fibrinogen (functional and immunological), fibrinopeptide A, thrombinantithrombin III complex, and D-dimer were measured. The severity of atherosclerosis was associated with both fibrinogen (both functional and immunological) and D-dimer (r=.57,p<.0002, and r=.S7, /><.0001, respectively). Fibrinogen and D-dimer showed a significant positive correlation (r=.5O,p<.001). Generation of thrombin was detected in 24 patients (60%) by fibrinopeptide A and levels of thrombinantithrombin III complex. As a sign of coagulation activation and fibrinolysis, we found that thrombinantithrombin III complex and the degradation of cross-linked fibrin were progressively associated with the extent of vascular disease. The plasmin-mediated fibrin breakdown contributed to increased levels of circulating fibrinogen, an established risk factor for thrombotic complications. The significant correlations between fibrinogen/D-dimer and the severity of atherosclerosis support previous pathological studies and imply that local degradation of cross-linked fibrin is involved in the progression of atherosclerosis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Apolipoprotein B-100 (apoB-100) appears in three forms in the endoplasmic reticulum of Hep G2 cells: (1) tightly bound to the membrane, ie, not extractable by sodium carbonate. This form is glycosylated but protease sensitive when present in intact microsomes, suggesting that it is only partially translocated to the microsomal lumen; (2) extractable by sodium carbonate and present on low-density lipoprotein-verylow-density lipoprotein (LDL-VLDL)-like particles. This form is glycosylated and secreted into the medium; and (3) extractable by sodium carbonate but having a higher density than the LDL-VLDL-like particles. This form, referred to as Fraction I, is glycosylated and protected against proteases when present in intact microsomal vesicles, indicating that it is completely translocated to the luminal side of the microsomal membrane. Fraction I is not secreted into the medium, but it disappears with time from the cell, suggesting that it is degraded. Oleic acid induced a 2.7-fold increase in the rate of the biosynthesis of triacylglycerol but not of phosphatidylcholine in Hep G2 cells. Incubation of the cells with oleic acid had no significant effect on the rate of initiation of the apoB-100-containing lipoproteins, nor did it influence the amount of apoB-100 that was associated with the membrane or the turnover of apoB-100 in the membrane. Instead, it increased the proportion of the nascent apoB polypeptides on initiated lipoproteins that was converted into full-length apoB-100 on LDL-VLDL-like particles, giving rise to an increased amount of these particles in the lumen of the secretory pathway. Pulse-chase experiments showed that incubation with oleic acid gave rise to an increased formation of LDL-VLDL-like particles on behalf of the formation of Fraction I. This effect of oleic acid could partially explain the protective effect of the fatty acid on apoB-100, preventing it from undergoing posttranslational degradation.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

This study compared the effects of a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, fish oil, and placebo on plasma lipids and lipoproteins in patients with mixed hyperlipidemia. After an initial run-in phase, 32 patients were randomized for 6 weeks to either (1) pravastatin 40 nig/d, n=10; (2) fish 011 (himega 6 g/d, equivalent to 3 g to-3 fatty acids/d), n=10; or (3) placebo. After single drug therapy, in the pravastatin group mean total plasma cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B fell significantly by 23%p><.001), 30% (p<.001), and 26%pJ<.01), respectively. LDL Stokes' diameter did not change. In the fish oil group mean plasma triglycerides (TG) fell 30% (p<.05), LDL Stokes' diameter increased from 25.0 to 25.9 nm (p<.05), and there was a nonsignificant increase in LDL-C. There were no changes in the placebo group. To assess the effect of the combination of pravastatin plus fish oil therapy, all patients, except one woman from the placebo group who developed nausea on fish oil, then took combined therapy of pravastatin 40 mg/d plus fish oil 6 g/d for an additional 12 weeks. In each case, there were no clinically significant episodes of muscle tenderness or elevation of creatine phosphokinase or alanine aminotransferase. After 12 weeks of combined therapy of pravastatin plus fish oil, there were significant reductions in the mean TC, TG, LDL-C, and apoB in the three groups compared with baseline levels. High-density lipoprotein cholesterol (HDL-C) and apo A-1 did not change on any single or combined drug therapy. The effect of drug therapy on lipoprotein fractions was also determined. Lipoproteins of intermediate-density lipoprotein (IDL; Svedberg flotation units [Sf] 12 to 60) and very-low-density lipoprotein (VLDL; Sf>60) were isolated by ultracentrifugation. With pravastatin treatment, the concentration of VLDL and IDL did not change significantly, even though there was a trend toward a lower concentration of IDL lipids. With fish oil, the concentration of VLDL lipids fell significantly by at least 37%p><.05), whereas IDL remained unchanged. However, combined therapy of pravastatin plus fish oil reduced the concentration of both VLDL and IDL by at least 35% (bothp<.01). In addition, combined therapy reduced the TC-to-TG ratio in VLDL by 25% (p<.05). These results showed that in patients with mixed hyperlipidemia pravastatin lowered TC more than TG, whereas fish oil lowered TG but not TC. The combination of pravastatin plus fish oil reduced both TC and TG and appeared safe to use in the short term. Fish oil decreased the concentration of VLDL. However, the combination of pravastatin and fish oil effectively reduced the concentration of VLDL and IDL.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Our previous epidemiological studies have shown that levels of serum antibodies against mycobacterial heat-shock protein (hsp) 65 correlate positively with carotid atherosclerosis in subjects aged 40 to 79 years. To determine whether these high-titer sera also react with homologous human hsp60 and/or cell components of atherosclerotic lesions, we selected 15 human sera samples, each with high or low titers to recombinant mycobacterial hsp65, and investigated their reactivity with human arterial lesion components by immunoblotting and immunofluorescence techniques. All five higher-titer sera against hsp65 reacted with a 60-kDa band of atherosclerotic lesion proteins and human recombinant hsp60 on Western blots. Pooled sera with low antibody titers to hsp65 diluted similarly as high-titer sera did not show reactivity with atherosclerotic lesion and media proteins. By immunohistochemistry and immunofluorescence with human immunoglobulin G isolated from different sera, labeled with biotin, and visualized with a streptavidin conjugate, positive staining was observed in sections of fatty streaks and atherosclerotic plaques of carotid arteries, and weak staining was observed in the normal intima. Double immunofluorescence identified the majority of positively stained cells as macrophages, endothelial cells, and a few smooth muscle cells. In summary, serum antibodies against hsp65 cross-react with the human 60-kDa homologue present in high levels in atherosclerotic lesions and are mainly reacting with macrophages and endothelial cells, supporting our concept of a possible involvement of humoral-mediated immune reaction against hsp60 in atherogenesis.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Previous studies conducted within the framework of the Lipid Research Clinics Program showed a strong inverse correlation between high-density lipoprotein cholesterol (HDL-C) level and coronary heart disease (CHD) risk in American male populations, whereas in Russian populations such a correlation was less pronounced. It was assumed that HDL was less protective of CHD in Russian than in American males. This study compared the functional activity and lipid composition of HDL, isolated from the blood plasma of men with low, normal, and high HDL-C levels from Moscow (Russia) and Seattle (United States) populations. Results obtained showed that American HDL, irrespective of the plasma HDL-C level, had higher activity in stimulating both [3H] cholesterol and cholesterol mass efflux from cholesterol-loaded fibroblasts and in suppressing cellular cholesterol esterification when compared with Russian HDL,. American HDL, remained more active than Russian HDL, even when apolipoprotein E-containing particles were removed from HDL, by heparin-Sepharose affinity chromatography. Russian and American125I-HDL, had similar binding to high-affinity cell-surface sites, but Russian HDL, had a higher nonspecific binding component compared with American HDL,. This study demonstrates for the first time potential functional differences between HDL particles isolated from Russian and American populations. The lower activity of Russian HDL3in promoting cellular cholesterol efflux may partly explain the higher CHD risk in the Russian population compared with the American one.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

In previously reported in vitro studies, we found that heme, a physiologically widespread hydrophobic iron compound, can rapidly generate oxidized low-density lipoprotein (LDL), which then becomes cytotoxic to cultured vascular endothelial cells; both LDL oxidation and endothelial cytotoxicity were inhibited by incubation with exogenous a-tocopherol (vitamin E) or ascorbic acid (vitamin C). Seeking relevance to in vivo conditions, we performed a study in which 10 human volunteers were given daily antioxidant supplements of 800 IU of DL-<x-tocopherol acetate alone or in combination with 1000 mg of ascorbic acid for 2 weeks. LDL resistance to heme oxidation ex vivo, as measured by the lag time for conjugated-diene formation, increased by as much as threefold from a mean±SD of 58±11 to 104±18 minutes (p<.001); LDL a-tocopherol increased from 11 ±2 to 26±6 molecules per LDL particle (p<.001); and most impressively, cytotoxicity to porcine aortic endothelial cells incubated with LDL conditioned with heme plus H2O2or with copper was completely prevented (cytotoxicity before supplementation was 42 + 12%, decreasing after supplementation to 3±2%,p<.001). These measurements reverted to their presupplement levels within 2 weeks after participants stopped taking antioxidant supplements and were reproduced in 4 subjects taking 800 IU of DL-a-tocopherol acetate supplements alone but not in the same subjects taking 1000 mg ascorbic acid supplements alone. In conclusion, oral vitamin E supplementation increases LDL or-tocopherol content, increases LDL resistance to oxidation, and decreases the cytotoxicity of oxidized LDL to cultured vascular endothelial cells.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

The susceptibility of low-density lipoprotein (LDL) to oxidation was studied in hypertriglyceridemic men (5 with type III and 5 with type IV) at baseline on a low-saturated-fat, low-cholesterol diet, after 6 weeks of dietary supplementation with fish oil (Promega, 12 g/d), and after 6 weeks of fish oil combined with probucol (500 mg BID). The relative content of n-3 polyunsaturated fatty acids in plasma and LDL was increased during the two treatment periods, and a low a-tocopherol to n-3 polyunsaturated fatty acids ratio was observed. Plasma thiobarbituric acid-reactive substances (TBARS) levels were unchanged after 6 weeks of fish oil, but the ratio of lipid peroxides to the reduced triglyceride (TG) levels (MDA: TG) was significantly higher (p<.01). Addition of probucol lowered both absolute levels of TBARS (p<.01) and the MDA to TG ratio (p<.001). The susceptibility of LDL to Cu2+-catalyzed oxidation was evaluated over a 5-hour time course by determining TBARS formation, free amino group levels, and changes in LDL electrophoretic mobility. TBARS levels that were higher in native LDL (1.019«/< 1.050 g/mL) after 6 weeks offish oil than at baseline (p<.0l) were reduced 52.3±11.3% by the addition of probucol (p<.001). With fish oil alone, TBARS production after exposure of LDL to Cu2+for 5 hours was increased 17.0±5.8% compared with corresponding baseline values (p<.001), whereas a 64.1 ±14.3% reduction from the previous period was observed with fish oil+probucolp><.001). Determination of LDL reactive amino groups further documented the structural changes occurring with peroxide formation, which were opposed by probucol. Our observations emphasize a potential risk associated with intake of large doses of fish oil in the treatment of hyperlipidemia and further demonstrate the ability of probucol as an antioxidant.

ISSN:1049-8834    

出版商:OVID    

年代:1993

数据来源: OVID