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1.
Scavenger receptor-mediated uptake of oxidized LDL (oxLDL) is thought to be the major mechanism of foam cell generation in atherosclerotic lesions. Recent data has indicated that native LDL is also capable of contributing to foam cell formation via low-affinity receptor-independent LDL particle pinocytosis and selective cholesteryl ester (CE) uptake. In the current investigation, Cu2+-induced LDL oxidation was found to inhibit macrophage selective CE uptake. Impairment of selective CE uptake was significant with LDL oxidized for as little as 30 min and correlated with oxidative fragmentation of apoB. In contrast, LDL aggregation, LDL CE oxidation, and the enhancement of scavenger receptor-mediated LDL particle uptake required at least 3 h of oxidation. Selective CE uptake did not require expression of the LDL receptor (LDL-R) and was inhibited similarly by LDL oxidation in LDL-R−/− versus WT macrophages. Inhibition of selective uptake was also observed when cells were pretreated or cotreated with minimally oxidized LDL, indicating a direct inhibitory effect of this oxLDL on macrophages. Consistent with the effect on LDL CE uptake, minimal LDL oxidation almost completely prevented LDL-induced foam cell formation. These data demonstrate a novel inhibitory effect of mildly oxidized LDL that may reduce foam cell formation in atherosclerosis.  相似文献   

2.
The oxidation of low-density lipoprotein (LDL) induces immunogenic epitopes, many of which are due to oxidatively modified phospholipids (oxPL). Lysophosphatidylcholine (lyso-PC) which is generated during LDL oxidation through the hydrolysis of oxPL by LDL-associated PAF-acetylhydrolase (PAF-AH) is also immunogenic. We investigated whether the LDL-associated PAF-AH and the extent of LDL oxidation influence the autoantibody titers against oxidized LDL (oxLDL) in patients with stable angina as well as in apparently healthy volunteers. Three types of copper-oxidized LDL, were prepared at the end of the lag, propagation or decomposition phase (oxLDL(L), oxLDL(P) and oxLDL(D), respectively). Similar types of oxidized LDL were prepared after previous inactivation of endogenous PAF-AH [oxLDL(-)]. All these types of oxLDL as well as malondialdehyde-modified LDL (MDA-LDL) were used as antigens. Antibody titers against the above antigens were measured with an ELISA method in the serum of 65 patients with stable angina and 47 apparently healthy volunteers. Both groups exhibited higher autoantibody titers against each type of oxLDL(-) compared to the respective type of oxLDL (P<0.00001). In both groups autoantibody titers were higher when the oxLDL(P) and oxLDL(D) or oxLDL(-)(P) and oxLDL(-)(D) were used as antigens compared to oxLDL(L) (P<0.04) or to oxLDL(-)(L), respectively (P<0.0001 for all comparisons). Patients had significantly higher titers against all types of oxLDL (enriched in lyso-PC) and oxLDL(-) (enriched in intact oxPL) compared to controls. Autoantibody titers against MDA-LDL did not differ between patients and controls. Multivariate logistic regression analysis showed that among the autoantibody titers measured only those towards oxLDL(P) are associated with a significantly higher risk for coronary artery disease. LDL-associated PAF-AH activity may play an important role in decreasing the overall immunogenicity of oxLDL, whereas the extent of LDL oxidation seems to modulate the epitopes formed on oxLDL. Lyso-PC, a major component of oxLDL(P), could be mainly responsible for the elevated autoantibody titers against oxLDL in patients with stable angina.  相似文献   

3.
Death of macrophages and smooth muscle cells (SMC) can lead to progression of atherosclerosis. Mildly oxidised low-density lipoprotein (mildly-oxLDL) induced more overall death and apoptosis than moderately oxidised LDL, in human monocyte-macrophages (HMM). Mildly-oxLDL also induced more overall death in human SMC than did moderately-oxLDL. Mildly-oxLDL contained more hydroperoxides, but less oxysterol, malondialdehyde and negative charge than moderately-oxLDL. Specific inhibition of lipoprotein-associated phospholipase A(2) (by SB222657) diminished death induction in HMM by both oxLDL types. Peroxisome proliferator-activated receptor gamma (PPARgamma) antagonist (GW9662) and agonist (ciglitazone) experiments suggested that non-hydrolysed, oxidised phospholipids in oxLDL activate PPARgamma as a cellular defence mechanism. These results may be relevant to LDL oxidation within atherosclerotic plaques and may suggest strategies for combating atherosclerosis progression.  相似文献   

4.
Endothelial dysfunction is an early manifestation of atherosclerosis caused in part by oxidized LDL (oxLDL). Since vitamin C, or ascorbic acid, prevents several aspects of endothelial dysfunction, the effects of oxLDL on oxidative stress and regulation of the ascorbate transporter, SVCT2, were studied in cultured EA.hy926 endothelial cells. Cells cultured for 18 h with 0.2 mg/ml oxLDL showed increased lipid peroxidation that was prevented by a single addition of 0.25 mM ascorbate at the beginning of the incubation. This protection caused a decrease in intracellular ascorbate, but no change in the cell content of GSH. In the absence of ascorbate, oxLDL increased SVCT2 protein and function during 18 h in culture. Although culture of the cells with ascorbate did not affect SVCT2 protein expression, the oxLDL-induced increase in SVCT2 protein expression was prevented by ascorbate. These results suggest that up-regulation of endothelial cell SVCT2 expression and function may help to maintain intracellular ascorbate during oxLDL-induced oxidative stress, and that ascorbate in turn can prevent this effect.  相似文献   

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8.
Recent data suggest an inverse epidemiological association between intake of flavanol-rich cocoa products and cardiac mortality. Potential beneficial effect of cocoa may be attributed to flavanol-mediated improvement of endothelial function, as well as to enhancement of bioavailability and bioactivity of nitric oxide in vivo. ( - )-Epicatechin is one bioactive flavanol found in cocoa. This review deals with protective actions of ( - )-epicatechin on two key processes in atherogenesis, oxidation of LDL and damage to endothelial cell by oxidized LDL (oxLDL), with emphasis on data from this laboratory. ( - )-Epicatechin not only abrogates or attenuates LDL oxidation but also counteracts deleterious actions of oxLDL on vascular endothelial cells. These protective actions are only partially shared by other vasoprotective agents such as vitamins C and E or aspirin. Thus, ( - )-epicatechin appears to be a pleiotropic protectant for both LDL and endothelial cells.  相似文献   

9.
INTRODUCTION: The aim of this study was to evaluate the influence of hypothyroidism on oxidative modification of low density lipoprotein (LDL). MATERIAL AND METHODS: 24 patients with overt hypothyroidism and 10 patients with mild hypothyroidism were enrolled to the study. The control group consisted of 24 healthy subjects with normal serum TSH. Plasma level of oxidized LDL (oxLDL) and serum level of antibodies against oxidized LDL (anti-oxLDL) determined lipoprotein oxidation. RESULTS: Significantly increased plasma oxLDL levels were found in patients with overt hypothyroidism in comparison to patients with mild hypothyroidism and control group. Anti-oxLDL levels in patients with overt or mild hypothyroidism and in the control group showed no significant differences. OxLDL plasma levels in patients with hypothyroidism inversely correlated with FT(4) levels and positively correlated with TSH, total cholesterol, LDL cholesterol and triglycerides levels. CONCLUSIONS: The presented study indicates increased lipoprotein oxidation in patients with hypothyroidism which depends on the degree of hypothyroidism and changes in lipid profile. Elevated cholesterol and triglycerides levels are the factors increasing lipoprotein oxidation. Plasma oxLDL levels may constitute a useful marker indicating the risk for atherosclerosis in hypothyroidism.  相似文献   

10.
The oxidative modification of low-density lipoprotein (LDL) and subsequent alteration of endothelial cell function are generally accepted as an important early event in the pathogenesis of atherosclerosis. To understand the mechanism by which oxidized LDL (oxLDL) causes dysfunction in endothelial cells, human umbilical vein endothelial cells (HUVEC) were exposed to oxLDL at a concentration that induces cellular dysfunction, and proteomic analysis was carried out, together with the analysis of cellular lipid peroxidation products. Time-dependent accumulation of 7-ketocholesterol and the progression of oxidative modification of peroxiredoxin 2 were observed, together with the suppression of cell proliferation. Proteomic analysis using two-dimensional gel electrophoresis (2-D gel) revealed that nucleophosmin, stathmin, and nucleolin were differentially expressed after exposure to oxLDL. Both 2-D gel and western blot analyses revealed that (1) nucleophosmin was dephosphorylated in a time-dependent manner; (2) stathmin was transiently phosphorylated at 6 h, and the unphosphorylated form was continuously down-regulated; and (3) nucleolin was identified as a 20-kDa fragment and a 76-kDa form, which were down-regulated. These observations suggest that the exposure of HUVEC to oxLDL results in the suppression of cell proliferation, which is ascribed to protein modification and/or altered expression of nucleophosmin, stathmin, and nucleolin under these oxidative stress conditions.  相似文献   

11.
The oxidative modification of low-density lipoprotein (LDL) and subsequent alteration of endothelial cell function are generally accepted as an important early event in the pathogenesis of atherosclerosis. To understand the mechanism by which oxidized LDL (oxLDL) causes dysfunction in endothelial cells, human umbilical vein endothelial cells (HUVEC) were exposed to oxLDL at a concentration that induces cellular dysfunction, and proteomic analysis was carried out, together with the analysis of cellular lipid peroxidation products. Time-dependent accumulation of 7-ketocholesterol and the progression of oxidative modification of peroxiredoxin 2 were observed, together with the suppression of cell proliferation. Proteomic analysis using two-dimensional gel electrophoresis (2-D gel) revealed that nucleophosmin, stathmin, and nucleolin were differentially expressed after exposure to oxLDL. Both 2-D gel and western blot analyses revealed that (1) nucleophosmin was dephosphorylated in a time-dependent manner; (2) stathmin was transiently phosphorylated at 6 h, and the unphosphorylated form was continuously down-regulated; and (3) nucleolin was identified as a 20-kDa fragment and a 76-kDa form, which were down-regulated. These observations suggest that the exposure of HUVEC to oxLDL results in the suppression of cell proliferation, which is ascribed to protein modification and/or altered expression of nucleophosmin, stathmin, and nucleolin under these oxidative stress conditions.  相似文献   

12.
In blood circulation, low density lipoproteins (LDL) can undergo modification, such as oxidation, and become key factors in the development of atherosclerosis. Although the liver is the major organ involved in the elimination of oxidized LDL (oxLDL), the identity of the receptor(s) involved remains to be defined. Our work aims to clarify the role of the scavenger receptor class B type I (SR-BI) in the hepatic metabolism of mildly and standardly oxLDL as well as the relative contribution of parenchymal (hepatocytes) and nonparenchymal liver cells with a special emphasis on CE-selective uptake. The association of native LDL and mildly or standardly oxLDL labeled either in proteins or in cholesteryl esters (CE) was measured on primary cultures of mouse hepatocytes from normal and SR-BI knock-out (KO) mice. These in vitro assays demonstrated that hepatocytes are able to mediate CE-selective uptake from both LDL and oxLDL and that SR-BI KO hepatocytes have a 60% reduced ability to selectively take CE from LDL but not towards mildly or standardly oxLDL. When lipoproteins were injected in the mouse inferior vena cava, parenchymal and nonparenchymal liver cells accumulated more CE than proteins from native, mildly and standardly oxLDL, indicating that selective uptake of CE from these lipoproteins occurs in vivo in these two cell types. The parenchymal cells contribute near 90% of the LDL-CE selective uptake and SR-BI for 60% of this pathway. Nonparenchymal cells capture mainly standardly oxLDL while parenchymal and nonparenchymal cells equally take up mildly oxLDL. An 82% reduction of standardly oxLDL-CE selective uptake by the nonparenchymal cells of SR-BI KO mice allowed emphasizing the contribution of SR-BI in hepatic metabolism of standardly oxLDL. However, SR-BI is not responsible for mildly oxLDL metabolism. Thus, SR-BI is involved in LDL- and standardly oxLDL-CE selective uptake in parenchymal and nonparenchymal cells, respectively.  相似文献   

13.
Previous studies have shown that oxidation of low-density lipoprotein (oxLDL) results in its recognition by scavenger receptors on macrophages. Whereas blockage of lysyl residues on apoB-100 of oxLDL by lipid peroxidation products appears to be critical for recognition by the scavenger receptor class A (SR-A), modification of the lipid moiety has been suggested to be responsible for recognition by the scavenger class B receptor, CD36. We studied the recognition by scavenger receptors of oxidized LDL in which lysyl residues are blocked prior to oxidation through methylation [ox(m)LDL]. This permits us to minimize any contribution of modified apoB-100 to the recognition of oxLDL, but does not disrupt the native configuration of lipids in the particle. We found that ox(m)LDL was recognized by receptors on mouse peritoneal macrophages (MPM) almost as well as oxLDL. Ox(m)LDL was recognized by CD36-transfected cells but not by SR-A-transfected cells. Oxidized phospholipids (oxPC) transferred from oxLDL or directly from oxPC to LDL, conveyed recognition by CD36-transfected cells, confirming that CD36 recognized unbound oxidized phospholipids in ox(m)LDL. Collectively, these results suggest that oxPC not adducted to apoB within the intact oxLDL particle are recognized by the macrophage scavenger receptor CD36, that these lipids are not recognized by SR-A, and that they can transfer from oxidized to unoxidized LDL and induce CD36 recognition.  相似文献   

14.
The effects of oxidised LDL (oxLDL) on cell proliferation, apoptosis and hormone-induced differentiation have been evaluated for the first time in 3T3-L1 preadipocytes. Unlike control cells, oxLDL-treated preadipocytes showed a high proliferation rate, a low apoptosis level, and an impaired differentiation process with an increased preadipocyte factor-1 (Pref-1) mRNA expression at late times. By silencing Pref-1 mRNA or inhibiting its expression with an increased dexamethasone concentration, differentiation occurred as usual, which demonstrates the key role of Pref-1 overexpression. The results suggest a specific action of oxLDL on the adipogenesis inhibitor Pref-1, as indicated also by its reappearance in mature adipocytes treated with oxLDL. The inhibitory effects of oxLDL on differentiation required oxLDL uptake by CD36, and were associated with lipoprotein lipids. These results point to oxLDL as a modulator of adipose tissue mass and as possible link between obesity and its clinical complications.  相似文献   

15.
Dietary flavonoid intake has been reported to be inversely associated with the incidence of coronary artery disease. To clarify the possible role of flavonoids in the prevention of atherosclerosis, we investigated the effects of some of these compounds, including fisetin, morin and myricetin, on the susceptibility of low-density lipoprotein (LDL) to oxidative modification and on oxLDL uptake in macrophages. The results demonstrated that fisetin had stronger inhibitory activity than the other two on inhibiting Cu(2+)-mediated LDL oxidation measured by thiobarbituric acid-reactive substances assay (TBARS), conjugated diene formation and electrophoretic mobility. The class B scavenger receptor, CD36, to which oxLDL binds, is present in atherosclerotic lesions. Treatment of U937-derived macrophages with myricetin (20 microM) significantly inhibited CD36 cell surface protein and mRNA expression (p<0.01). Fisetin, morin and myricetin (20 microM) also reduced the feed-forward induction of CD36 mRNA and surface protein expression by PPARgamma. The inhibition of CD36 by flavonols was mediated by interference with PPARgamma activation thus counteracting the deleterious autoamplification loop of CD36 expression stimulated by PPARgamma ligand. All three flavonols (10 and 20 microM) markedly decreased the uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanide perchlorate (DiI)-labeled oxLDL uptake in U937-derived macrophages dose-dependently. Current evidences indicate that fisetin, morin and myricetin not only prevent LDL from oxidation but also block oxLDL uptake by macrophages at least in part through reducing CD36 gene expression on macrophages. In conclusion, flavonols may play a role in ameliorating atherosclerosis.  相似文献   

16.
C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta2-glycoprotein I (beta2GPI), implicating oxLDL/beta2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/beta2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of atherosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta2GPI complexes correlated with total cholesterol and hemoglobin A1c. Thus, the generation of CRP/oxLDL/beta2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/beta2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.  相似文献   

17.
Habitual consumption of some Melanesian medicinal and food plants may influence atherosclerosis development via their antioxidant capacity at the endothelial level. Areca nut (AN; Areca catechu), piper inflorescence (PBI; Piper betle), betel quid (BQ), guava buds (GB; Psidium guajava), the leaves (NL), juice (NJ), fruit (NF), and root (NR) of noni (Morinda citrifolia), the propagules of raw (MBR), and cooked (MBC) mangrove (Bruguiera gymnorrhiza) were evaluated for their ability to scavenge the 1,1-diphenyl-2-picryl-hydrazyle (DPPH) radical, to protect human low-density lipoprotein (LDL) from Cu2+-catalyzed oxidation and to protect cultured bovine aortal endothelial cells (BAEC) from oxidized LDL (oxLDL)-induced cytotoxicity. Polyphenol-rich extracts AN, PBI, and BQ were potent DPPH scavengers, having similar activity to quercetin and able to protect LDL from oxidation in a dose-dependent manner at concentrations higher than 10 microg/mL, but were pro-oxidants at lower concentrations. These extracts were cytotoxic to BAEC at concentrations above 10 microg/mL and were unable to prevent oxLDL endotheliopathy. GB and NR at 10 mug/mL displayed both the ability to delay LDL oxidation and prevent oxLDL cytotoxicity, although the latter lacked the ability to scavenge the DPPH radical. At higher concentrations, however, both were cytotoxic in themselves. The remaining noni extracts NF, NJ, NL, and both mangrove extracts MBC and MBR were unable to protect LDL from oxidation at all tested concentrations, but were effective cytoprotective agents at 50 microg/mL. All extracts were able to prevent an oxLDL-mediated increase in intracellular aldehyde generation but had little effect on extracellular peroxidation as measured by thiobarbituric acid reactive substances (TBARS). On the basis of this model system, we conclude that the antioxidant benefits of AN, PBI, and BQ may be offset by their enhancement of their cytotoxic effects of oxLDL toward BAEC, whereas GB and low concentrations of noni and mangrove may be considered antiatherogenic. The discrepancies between our in vitro and cellular culture experiments emphasize the importance of experimental conditions in evaluating the antioxidant potential of crude plant extracts.  相似文献   

18.
The pathogenesis of nonalcoholic steatohepatitis (NASH), like that of atherosclerosis, involves lipid accumulation, inflammation and fibrosis. Recent studies suggest that oxidized LDL (oxLDL) may be a risk factor for NASH, but oxLDL levels were not directly measured in these studies. The aim of this study was to examine whether there was an association between electronegative LDL [LDL(−)], a mildly oxLDL found in the blood, and the development of NASH using two animal models. Golden Syrian hamsters and C57BL/6 mice were fed a high-fat, high-cholesterol (HFC) diet for 6 or 12 weeks, then liver lipid and histopathology, plasma lipoprotein profile and LDL(−) levels were examined. The HFC-diet-fed hamsters and mice had similar levels of hepatic lipid but different histopathological changes, with microvesicular steatosis, hepatocellular hypertrophy, inflammation and bridging fibrosis in the hamsters, but only in mild steatohepatitis with low inflammatory cell infiltration in the mice. It also resulted in a significant increase in plasma levels of LDL cholesterol and LDL(−) in hamsters, but only a slight increase in mice. Moreover, enlarged Kupffer cells, LDL(−) and accumulation of unesterified cholesterol were detected in the portal area of HFC-diet-fed hamsters, but not HFC-diet-fed mice. An in vitro study showed that LDL(−) from HFC-diet-fed hamsters induced TNF-α secretion in rat Kupffer cell through a LOX-1-dependent pathway. Our results strongly suggest that LDL(−) is one of the underlying causes of hepatic inflammation and plays a critical role in the development of NASH.  相似文献   

19.
Paraoxonase (PON-1) is a high-density lipoprotein (HDL) associated enzyme that hydrolyzes lipid peroxides in vitro, which may therefore protect against the onset of atherosclerosis. Heavy smokers are more exposed to oxidative stress and hence at high-risk for oxidative modification of LDL. Our hypothesis is that the anti-oxidative properties of PON-1 inhibit LDL oxidation, especially in populations exposed to high oxidative stress. We have studied the effects of PON-1 genotype and smoking to variation in oxidative status parameters and intima-media thickness (IMT), a surrogate marker of atherosclerosis. The contribution of two common polymorphisms in the PON-1 gene (Q192R and L55M) to LDL oxidizability, autoantibodies directed against oxLDL and IMT were studied in 207 male life-long smokers. Smokers were classified into average, heavy and excessive smokers based on pack years of cigarettes smoked. PON-1 genotype was not associated with autoantibodies to oxLDL, LDL oxidizability or IMT. Smoking was associated with IMT in subgroups with the high levels of LDL, but not in the population at large. The lack of association of PON-1 genotype with oxidative status parameters and IMT suggests that PON-1 is not a major inhibitor of LDL oxidation in a population of life-long smokers.  相似文献   

20.
Endothelial dysfunction plays an important role in the development of atherosclerosis. Elastin-derived peptides (EDP), hyperglycemia, hypercholesterolemia and oxidized LDL have a proven proatherosclerotic potential. Nitric oxide generated by endothelial nitric oxide synthase (eNOS; EC 1.14.13.39) is an important vasorelaxant. Here we studied the influence of those proatherosclerotic factors on eNOS gene and protein expression in artery-derived endothelial cells. Human umbilical artery endothelial cells (HUAEC) were incubated with or without: glucose (270 mg/dl), LDL (200 mg/dl), oxidized LDL (oxLDL 25 mg/dl) or κ-elastin (0.5 and 2.5 μg/ml). Gene expression was assessed by real time RT-PCR, whilst the eNOS protein by ELISA. In cells incubated with 2.5 μg/ml of κ-elastin, a 31 % increase of eNOS mRNA expression was observed, but the protein level remained unchanged. OxLDL, LDL and glucose decreased the eNOS protein level by 74 %, 37 % and 29 %, respectively. OxLDL decreased eNOS mRNA by 42 %. LDL non-significantly decreased eNOS mRNA expression. An elevated glucose level did not affect the eNOS mRNA expression. Hyperglycemia and an elevated level of LDL, particularly oxLDL, decreased the level of eNOS protein in endothelial cells. As κ-elastin did not decrease the expression of eNOS gene in HUAEC, the proatherogenic properties of elastin-derived peptides are unlikely to be due to their influence on eNOS.  相似文献   

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