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PubMed2004

Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation.

Hypercholesterolemic human LDL contains oxidized subfractions that have atherogenic properties. Paradoxically, atherosclerosis incidence is low in patients with primary biliary cirrhosis (PBC), a disease characterized by marked increases in plasma LDL, including the LDL subfraction lipoprotein-X (Lp-X). To investigate the mechanisms underlying this paradox, we first examined the propensity to oxidation of unfractionated LDL isolated from PBC patients. After prolonged incubation with copper, PBC-LDL failed to increase the oxidation index or electrophoretic mobility noted in control LDL. An admixture of PBC-LDL or Lp-X with control LDL prevented oxidation of the latter in a dose-dependent manner. PBC-LDL was also noncompetitive against copper-oxidized LDL (oxLDL) for binding with a murine monoclonal anti-oxLDL antibody in a competitive ELISA. OxLDL exerts its proapoptotic and antiangiogenic effects in part by inhibiting fibroblast growth factor 2 (FGF2) expression. Preincubation of oxLDL with PBC-LDL, but not control LDL, attenuated the inhibitory effects of oxLDL on FGF2 expression in cultured bovine aortic endothelial cells (ECs). The antioxidant and prosurvival properties of PBC-LDL diminished after the patients underwent orthotopic liver transplantation. These results suggest that Lp-X reduces LDL atherogenicity by preventing LDL oxidation to protect EC integrity in the presence of hypercholesterolemia. They also suggest that altering LDL composition may be as important as reducing LDL concentration in preventing or treating atherosclerosis.

Animals↗
PubMed1999

Inter-relationships between small, dense low-density lipoprotein (LDL), plasma triacylglycerol and LDL apoprotein B in an atherogenic lipoprotein phenotype in free-living subjects.

A predominance of small, dense low-density lipoprotein (LDL) is a major component of an atherogenic lipoprotein phenotype, and a common, but modifiable, source of increased risk for coronary heart disease in the free-living population. While much of the atherogenicity of small, dense LDL is known to arise from its structural properties, the extent to which an increase in the number of small, dense LDL particles (hyper-apoprotein B) contributes to this risk of coronary heart disease is currently unknown. This study reports a method for the recruitment of free-living individuals with an atherogenic lipoprotein phenotype for a fish-oil intervention trial, and critically evaluates the relationship between LDL particle number and the predominance of small, dense LDL. In this group, volunteers were selected through local general practices on the basis of a moderately raised plasma triacylglycerol (triglyceride) level (>1.5 mmol/l) and a low concentration of high-density-lipoprotein cholesterol (<1.1 mmol/l). The screening of LDL subclasses revealed a predominance of small, dense LDL (LDL subclass pattern B) in 62% of the cohort. As expected, subjects with LDL subclass pattern B were characterized by higher plasma triacylglycerol and lower high-density lipoprotein cholesterol (<1.1 mmol/l) levels and, less predictably, by lower LDL cholesterol and apoprotein B levels (P<0.05; LDL subclass A compared with subclass B). While hyper-apoprotein B was detected in only five subjects, the relative percentage of small, dense LDL-III in subjects with subclass B showed an inverse relationship with LDL apoprotein B (r=-0.57; P<0.001), identifying a subset of individuals with plasma triacylglycerol above 2.5 mmol/l and a low concentration of LDL almost exclusively in a small and dense form. These findings indicate that a predominance of small, dense LDL and hyper-apoprotein B do not always co-exist in free-living groups. Moreover, if coronary risk increases with increasing LDL particle number, these results imply that the risk arising from a predominance of small, dense LDL may actually be reduced in certain cases when plasma triacylglycerol exceeds 2.5 mmol/l.

Adult↗
PubMed2000

Oxidation of apolipoprotein B-100 in circulating LDL is related to LDL residence time. In vivo insights from stable-isotope studies.

5-Hydroxy-2-aminovaleric acid (HAVA) has been suggested to be a specific marker of oxidation of apolipoprotein (apo) B-100 proline (Pro) and arginine (Arg) side-chain residues in low density lipoprotein (LDL) in vitro. Here we describe the application of sensitive mass spectrometric techniques to the characterization of Pro/Arg-modified apoB-100 in LDL(1) (S(f) 7 to 12) and LDL(2) (S(f) 0 to 7) in vivo. We studied 7 subjects with familial defective apoB-100 (FDB) and 8 normolipidemic controls. In FDB subjects, the presence of a mutant apoB-100 (FDB(3500Q)) in LDL markedly reduced its affinity for the LDL receptor, leading to increased residence times (RTs) of LDL(1) (65+/-21 versus 32+/-12 hours, P<0.005) and LDL(2) (230+/-40 versus 53+/-7 hours, P:<0.001) when compared with controls, as determined by stable-isotope turnover studies. LDL(1) HAVA content was not different between the groups (FDB, 0.004+/-0. 001 mol/mol apoB-100 versus controls, 0.003+/-0.001 mol/mol apoB-100, P=0.200). LDL(2) HAVA content was higher in FDB subjects (0. 374+/-0.088 versus 0.013+/-0.002 mol/mol apoB-100, P<0.001). In both groups, LDL(2) HAVA was positively associated with LDL(2) RT (FDB, r=0.893, P:=0.003; controls, r=0.976, P=0.000) and negatively correlated with LDL(2) alpha-tocopherol content (FDB, r=-0.929, P=0. 003; controls, r=-0.903, P=0.002). No significant correlations could be found between LDL(1) HAVA, LDL(1) RT, and alpha-tocopherol, respectively. The low LDL(1) HAVA content observed in both FDB and control groups was thought to be due to the relatively lower RT as well as the higher alpha-tocopherol content of these lipoproteins. In contrast, LDL(2) seemed to be strongly prone to direct oxidation of apoB-100 in vivo. The longer these particles linger in the circulation, the more apoB-100 Pro/Arg residues become modified.

Adult↗
PubMed1999

Low density lipoprotein (LDL) binding affinity for the LDL receptor in hyperlipoproteinemia.

We measured the binding affinity of low density lipoprotein (LDL) for the LDL receptor in patients with various types of hyperlipoproteinemia and investigated the effects of LDL lipid composition and particle size on receptor affinity. LDL (1.019 < d < 1.063) was isolated by sequential ultracentrifugation from the serum of normolipidemic controls and patients with hyperlipoproteinemia. Patients with type IIa hyperlipoproteinemia had LDL with a similar receptor affinity to that of normal LDL. However, patients with hypertriglyceridemia (type IIb and type IV hyperlipoproteinemia) had LDL with a low receptor affinity, and the degree of the reduction in affinity paralleled the severity of the hypertriglyceridemia. The LDL of hypertriglyceridemic patients was rich in protein and triglycerides, had a low content of cholesterol and phospholipids, and was smaller than normal, thus resembling the atherogenic lipoprotein known as small, dense LDL. These abnormalities were observed even in patients with mild hypertriglyceridemia regardless of their serum cholesterol levels. The degree of alteration in LDL lipid composition and particle size was strongly associated with the reduction of LDL receptor affinity. We also examined the effects of two lipid-lowering agents (bezafibrate and probucol) on the characteristics of LDL. LDL receptor affinity was only improved when the lipid composition and particle size were normalized by drug therapy. Although it has been reported that decreased cholesteryl ester transfer protein (CETP) activity results in the formation of small LDL, plasma CETP activity was normal in the hyperlipoproteinemic patients and the normalization of LDL characteristics by drug therapy was not accompanied by an increase of CETP activity. Our results suggested that an abnormal lipid composition and/or small particle size might cause a decrease in the receptor affinity of LDL. These structural and functional abnormalities were reversed by drug therapy, underlining the importance of treating hypertriglyceridemia for the prevention of atherosclerosis.

Adult↗
PubMed1994

Platelet LDL receptor recognizes with the same apparent affinity both oxidized and native LDL. Evidence that the receptor-ligand complexes are not internalized.

We have recently demonstrated that the platelet low-density lipoprotein (LDL) receptor is immunologically different from the "classic" receptor of nucleated cells. We undertook the current studies to investigate the interaction of this receptor with oxidized LDL and to determine whether an endocytosis-mediated response is involved in the binding of LDL to platelets. The platelet LDL receptor recognized with the same affinity both native and oxidized LDL particles (IC50, 0.045 and 0.054 g/L; Kd, 45.8 and 65.9 nmol/L, respectively). The Hill coefficients of the displacement of 125I-LDL binding were -1.10 and -1.05 for unlabeled native and oxidized LDL, respectively, thereby suggesting a single set of binding sites. To ascertain whether human platelets bind oxidized LDL, we performed ligand binding assays with 125I-oxidized LDL. Saturation curves of 125I-oxidized LDL binding at 22 degrees C showed that human platelets bound these modified particles to a class of saturable binding sites, numbering approximately 3895 +/- 241 per platelet with a dissociation constant (Kd) of 96.2 +/- 10.3 nmol/L. Displacement experiments showed that 125I-oxidized LDL binding was inhibited with the same affinity by both oxidized and native LDL (IC50, 0.055 and 0.065 g/L; Kd, 88 and 64 nmol/L, respectively). The Hill coefficients of the displacement of the 125I-oxidized LDL binding were -1.02 and -1.07 for unlabeled oxidized and native LDL, respectively, suggesting that a single set of binding sites is implicated. Moreover, oxidized LDL- at a protein concentration of 0.5 g/L enhanced ADP- and collagen-induced platelet aggregation in a manner similar to native LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1998

Influence of apoE content on receptor binding of large, bouyant LDL in subjects with different LDL subclass phenotypes.

We investigated the influence of apolipoprotein (apo) E-containing particles on LDL receptor binding of large, buoyant LDL subfractions (LDL I) from subjects with predominantly large (phenotype A) and small (phenotype B) LDL particles. Direct binding by human fibroblast LDL receptors was tested at 4 degrees C before and after removal of apoE-containing particles by immunoaffinity chromatography. The binding affinity of total LDL I in phenotype B was greater than that in phenotype A (Kd of 1.83+/-0.3 and 3.43+/-0.9 nmol/L, respectively, P<.05). LDL I from phenotype B subjects had a higher apoE to apoB molar ratio than did that from phenotype A (0.16+/-0.04 versus 0.06+/-0.02, P<.05). Nondenaturing gradient gel electrophoresis of apoE-containing LDL I isolated by immunoaffinity chromatography revealed a substantially larger peak particle diameter than in apoE-free LDL I, and comparison of LDL I composition before and after immunoaffinity chromatography suggested an increase in triglyceride content of apoE-containing particles. After removal of these particles, there was a greater than twofold reduction in LDL receptor affinity of phenotype B LDL (Kd of 1.83+/-0.3 to 3.76+/-0.6, P<.01), whereas in phenotype A no change was observed (Kd of 3.43+/-0.9 to 3.57+/-0.4, respectively). The receptor affinity of apoE-free LDL I from phenotype A and B subjects did not differ. These findings confirm that large, buoyant LDL particles from phenotype B subjects have a higher LDL receptor affinity than does LDL I from phenotype A subjects and suggest that this difference is due to an increased content of large, triglyceride-enriched, apoE-containing lipoproteins. It is possible that the accumulation of these particles reflects abnormalities in the metabolism of remnant lipoproteins that contribute to atherosclerosis risk in phenotype B subjects.

Adult↗
PubMed1994

Conformational differences in human apolipoprotein B-100 among subspecies of low density lipoproteins (LDL). Association of altered proteolytic accessibility with decreased receptor binding of LDL subspecies from hypertriglyceridemic subjects.

We asked at what point in the metabolic cascade of very low density lipoproteins (VLDL) to low density lipoproteins (LDL) the accessibility of proteolytic cleavage sites in B-100 changes, and we evaluated the effect of hypertriglyceridemia on the proteolytic accessibility, secondary structure, and receptor-binding affinity of B-100 in LDL subspecies of varying density. Limited proteolysis with Staphylococcus aureus V8 protease and cathepsin D identified the density (about 1.033 g/ml) between two LDL subspecies, designated LDL-1 and -2, as the transition point during VLDL metabolism of both normolipidemic (N-) and hypertriglyceridemic (HTG-) subjects at which accessibility to protease attack changed in three peptide regions of B-100. Hypertriglyceridemia greatly altered proteolytic accessibility of B-100 in the denser LDL subspecies. Specifically, B-100 in HTG-LDL exposed more cleavage sites than in N-LDL, including two novel sites, approximately 120 and approximately 130 kDa from the NH2 terminus in the small and dense subspecies (designated LDL-4, -4.5 or -5, d = 1.048-1.062 g/ml). Analysis of circular dichroic spectra indicated no difference in helical content between B-100 in N- and HTG-LDL but showed a greater content of beta-structure in HTG-LDL. Binding affinity for the LDL receptor of human fibroblasts decreased markedly with increasing density among HTG-LDL subspecies (by approximately 50% for LDL-4.5 or -5). We conclude that the changes in proteolytic accessibility observed between LDL-1 and -2 and in LDL-4, -4.5, or -5 indicate significant differences in local conformation of B-100 at specific peptide regions. The association of exposure of more cleavage sites, especially novel sites in the NH2-terminal regions, with greatly decreased receptor-binding affinity in LDL-4.5 or -5 suggests that altered local conformation in B-100 apart from the putative receptor-binding domain might affect interaction with the receptor.

Apolipoprotein B-100↗
PubMed2004

Positive correlation between in vivo oxidized LDL and LDL immune complexes.

OBJECTIVES: To investigate the possible relationship between oxidized low-density lipoprotein (ox-LDL) and LDL immune complexes (IC). METHODS: Both LDL-IC and ox-LDL were detected by sandwich ELISA. The levels were also studied in 60 patients with coronary heart disease (CHD) and 50 control subjects. RESULTS: Compared to controls, both the plasma ox-LDL concentrations (595.5 +/- 194.8 vs. 440.3 +/- 175.0 microg/l, P < 0.001) and LDL-IC levels (2.74 +/- 0.73 vs. 1.38 +/- 0.78 AU, P < 0.001) in the patients with CHD were significantly increased. The relationships between LDL-IC, ox-LDL levels, and other lipid parameters in all the studied subjects (n = 100) were analyzed. LDL-IC levels were positively correlated with TC, TG, LDL-C, lipoprotein(a) [Lp(a)], and apolipoprotein B (apoB) concentration, while negatively correlated with apoA1 concentration, respectively. Similarly, ox-LDL levels were also found positively correlated with TC, LDL-C, and apoB concentrations, respectively. Furthermore, a significantly positive correlation between ox-LDL and LDL-IC levels was found (r = 0.313, P < 0.005). CONCLUSION: In vivo oxidized LDL positively correlates with circulating levels of LDL immune complexes.

Antigen-Antibody Complex↗
PubMed2001

Immunological response to oxidized LDL occurs in association with oxidative DNA damage independently of serum LDL concentrations in dyslipidemic patients.

Oxidative modification of LDL induces immunogenic epitopes in the LDL molecule, and the presence of antibodies against oxidized LDL (anti-Ox-LDL) has been demonstrated in human sera. However, little is known about the clinical significance of anti-Ox-LDL. To elucidate a clinical relationship between the immunological response to oxidized LDL and cellular oxidative stress, we measured serum titers of anti-Ox-LDL in 45 unselected patients with hypercholesterolemia and serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), considered a biomarker of the oxidative damage to DNA. The anti-Ox-LDL titer was not correlated with the serum LDL-C concentration, but was correlated with the 8-OHdG concentration (r = 0.300, P < 0.05) in a simple linear regression. Multiple regression analysis indicated that 8-OHdG was independently correlated with anti-Ox-LDL (r = 0.429, P < 0.05), but no other variables, including LDL-C concentrations and smoking habit, were correlated with anti-Ox-LDL. In 16 subgroup patients, the concentrations of TC, TG and LDL-C decreased and the HDL-C concentration increased after cholesterol-lowering therapy with fluvastatin. In addition, both the anti-Ox LDL titer (14.0 +/- 9.5 to 11.4 +/- 6.6 AcU/ml, P < 0.05) and the 8-OHdG concentration (1.19 +/- 0.41 to 0.85 +/- 0.43 ng/ml, P < 0.05) also decreased after fluvastatin therapy. The immunological response to LDL oxidation on vascular wall tissues or cells appear to occur in association with oxidative DNA damage. The measurement of anti-Ox-LDL may be a useful indicator for lipid-lowering therapy.

Anticholesteremic Agents↗
PubMed1997

Reduced susceptibility of low density lipoprotein (LDL) to lipid peroxidation after fluvastatin therapy is associated with the hypocholesterolemic effect of the drug and its binding to the LDL.

Increased plasma cholesterol concentration in hypercholesterolemic patients is a major risk factor for atherosclerosis. The impaired removal of plasma low density lipoprotein (LDL) in these patients results in the presence of their LDL in the plasma for a long period of time and thus can contribute to its enhanced oxidative modification. In the present study we analyzed the effect of the hypocholesterolemic drug, fluvastatin, on plasma and LDL susceptibilities to oxidation during 24 weeks of therapy. Fluvastatin therapy (40 mg/day for 24 weeks) in 10 hypercholesterolemic patients resulted in 30%, 34% and 22% decrements in plasma levels of total cholesterol, LDL cholesterol and triglycerides, respectively. This effect has been achieved after only 4 weeks of therapy. We next studied the effect of fluvastatin therapy on LDL susceptibility to oxidation in vivo and in vitro. 2.2-Azobis, 2-amidinopropane hydrochloride (AAPH, 100 mM)-induced plasma lipid peroxidation was decreased by 70% and 77% after 12 weeks and 24 weeks of fluvastatin therapy respectively. The lag time required for the initiation of CuSO4 (10 microM)-induced LDL oxidation was prolonged by 1.2- and 2.5-fold, after 12 and 24 weeks of fluvastatin therapy respectively. We next analyzed the in vitro effect of fluvastatin on plasma and LDL susceptibilities to oxidation. Preincubation of plasma or LDLs that were obtained from normal subjects with 0.1 microgram/ml of fluvastatin, caused 20% or 57% reduction in AAPH-induced lipid peroxidation, respectively. Similarly, a 1.6- and 2.7-fold prolongation of the lag time required for CuSO4-induced LDL oxidation was found following LDL incubation with 0.1 and 1.0 microgram/ml of fluvastatin, respectively. To find out possible mechanisms that contribute to this inhibitory effect of fluvastatin on LDL oxidizability, we analyzed the antioxidative properties of fluvastatin. Fluvastatin did not scavenge free radicals and did not inhibit linoleic acid peroxidation. Fluvastatin also did not act as a chelator of copper ions. However, fluvastatin was shown to specifically bind mainly to the LDL surface phospholipids and this interaction altered the lipoprotein charge as evident from the 38% decrement in the electrophoretic mobility of fluvastatin-treated LDL, in comparison to nontreated LDL. The inhibitory effect of fluvastatin therapy on LDL oxidation probably involves both its stimulatory effect on LDL removal from the circulation, as well as a direct binding effect of the drug to the lipoprotein. We thus conclude that the antiatherogenic properties of fluvastatin may not be limited to its hypocholesterolemic effect, but could also be related to its ability to reduce LDL oxidizability.

Adult↗
PubMed1999

Inhibition of copper-induced LDL oxidation by vitamin C is associated with decreased copper-binding to LDL and 2-oxo-histidine formation.

Oxidatively modified low-density lipoprotein (LDL) has numerous atherogenic properties, and antioxidants that can prevent LDL oxidation may act as antiatherogens. We have previously shown that vitamin C (L-ascorbic acid, AA) and its two-electron oxidation product dehydro-L-ascorbic acid (DHA) strongly inhibit copper (Cu)-induced LDL oxidation. These findings are unusual, as AA is known to act not only as an antioxidant, but also a pro-oxidant in the presence of transition metal ions in vitro, and DHA has no known reducing capacity. Here we report that human LDL (0.4 mg protein/ml) incubated with 40 microM Cu2+ binds 28.0 +/- 3.3 Cu ions per LDL particle (mean +/- SD, n = 10). Co-incubation of LDL with AA or DHA led to the time- and concentration-dependent release of up to 70% of bound Cu, which was associated with the inhibition of LDL oxidation. Incubation of LDL with Cu and AA or DHA also led to the time-dependent formation of 2-oxo-histidine, an oxidized derivative of histidine with a low affinity for Cu. Addition of free histidine prevented the formation of the LDL-Cu complexes and inhibited LDL oxidation, despite the fact that Cu remained redox-active. Interestingly, histidine was more effective than AA or DHA at limiting Cu binding to LDL, but at low concentrations AA and DHA were more effective than histidine at inhibiting LDL oxidation. These data suggest that there are at least two types of Cu binding sites on LDL: those that bind Cu in a redox-active form critical for initiation of LDL oxidation, and those that bind Cu in a redox-inactive form not contributing to LDL oxidation. The former sites may be primarily histidine residues of apolipoprotein B-100 that are oxidized to 2-oxo-histidine in the presence of Cu and AA or DHA, thus explaining, at least in part, the unusual inhibitory effect of vitamin C on Cu-induced LDL oxidation.

Antioxidants↗
PubMed1999

Baseline diene conjugation in LDL lipids: an indicator of circulating oxidized LDL.

The wide acceptance of the diene conjugation-method in monitoring low-density lipoprotein (LDL) oxidation ex vivo has led to development of an assay, which measures the amount of baseline diene conjugation (BDC) in circulating LDL, and is an indicator of oxidized LDL in vivo. The LDL-BDC assay is based on precipitation of serum LDL with buffered heparin, and spectrophotometric determination of baseline level of conjugated dienes in lipids extracted from LDL. Compared to existing methods for oxidized LDL, LDL-BDC is fast and simple to perform. Chemical studies by HPLC and NMR have verified that LDL-BDC is a specific indicator of circulating mildly oxidized LDL. Validity of the assay is further indicated by strong correlation with the titer of autoantibodies against oxidized LDL. Clinical studies have shown that LDL-BDC is closely related to coronary, carotid, and brachial atherosclerosis. Moreover, several independent studies have demonstrated surprisingly strong associations between LDL-BDC and known atherosclerosis risk factors (obesity, physical inactivity, hypertension, diabetes, and arterial functions). Indeed, these studies seem to indicate that as an indicator of the risk of atherosclerosis LDL-BDC clearly exceeds sensitivity and specificity of the common lipid markers of atherosclerosis. It is concluded that LDL-BDC is a promising candidate in search for methods for the evaluation of in vivo LDL oxidation and the risk of atherosclerosis.

Arteriosclerosis↗
PubMed1988

Uptake of LDL in parenchymal and non-parenchymal rabbit liver cells in vivo. LDL uptake is increased in endothelial cells in cholesterol-fed rabbits.

1. Hepatic uptake of low-density lipoprotein (LDL) in parenchymal cells and non-parenchymal cells was studied in control-fed and cholesterol-fed rabbits after intravenous injection of radioiodinated native LDL (125I-TC-LDL) and methylated LDL (131I-TC-MetLDL). 2. LDL was taken up by rabbit liver parenchymal cells, as well as by endothelial and Kupffer cells. Parenchymal cells, however, were responsible for 92% of the hepatic LDL uptake. 3. Of LDL in the hepatocytes, 89% was taken up via the B,E receptor, whereas 16% and 32% of the uptake of LDL in liver endothelial cells and Kupffer cells, respectively, was B,E receptor-dependent. 4. Cholesterol feeding markedly reduced B,E receptor-mediated uptake of LDL in parenchymal liver cells and in Kupffer cells, to 19% and 29% of controls, respectively. Total uptake of LDL in liver endothelial cells was increased about 2-fold. This increased uptake is probably mediated via the scavenger receptor. The B,E receptor-independent association of LDL with parenchymal cells was not affected by the cholesterol feeding. 5. It is concluded that the B,E receptor is located in parenchymal as well as in the non-parenchymal rabbit liver cells, and that this receptor is down-regulated by cholesterol feeding. Parenchymal cells are the main site of hepatic uptake of LDL, both under normal conditions and when the number of B,E receptors is down-regulated by cholesterol feeding. In addition, LDL is taken up by B,E receptor-independent mechanism(s) in rabbit liver parenchymal, endothelial and Kupffer cells. The non-parenchymal liver cells may play a quantitatively important role when the concentration of circulating LDL is maintained at a high level in plasma, being responsible for 26% of hepatic uptake of LDL in cholesterol-fed rabbits as compared with 8% in control-fed rabbits. The proportion of hepatic LDL uptake in endothelial cells was greater than 5-fold higher in the diet-induced hypercholesterolaemic rabbits than in controls.

Animals↗
PubMed2002

Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study).

OBJECTIVES: Hypothetically the atherogenic effect of the metabolic syndrome may be mediated through the increased occurrence of small LDL-particles which are easily modified to atherogenic oxidized LDL (ox-LDL). The aim of this study was to test this concept by examining the association between circulating ox-LDL, LDL-particle size, and the metabolic syndrome. DESIGN AND RESULTS: A population-based sample of clinically healthy 58-year-old men (n = 391) was recruited. Ox-LDL was measured by ELISA (specific monoclonal antibody, mAb-4E6) and LDL-particle size by gradient gel electrophoresis. The results showed that ox-LDL significantly correlated to factors constituting the metabolic syndrome; triglycerides (r = 0.43), plasma insulin (r = 0.20), body mass index (r = 0.20), waist-to-hip ratio (r = 0.21) and HDL (r = -0.24); (P < 0.001). Ox-LDL correlated also to LDL-particle size (r = -0.42), Apo-B (r = 0.70), LDL (r = 0.65); (P < 0.001) and, furthermore, with Apo A-1 (r = -0.13) and heart rate (r = 0.13); (P < 0.01). CONCLUSION: The metabolic syndrome was accompanied by high plasma ox-LDL concentrations compared with those without the syndrome. Ox-LDL levels were associated with most of the risk factors constituting the metabolic syndrome and was, in addition related to small LDL-particle size. To our knowledge the present study is the first one to demonstrate that circulating ox-LDL levels are associated with small LDL-particle size in a population representative sample of clinically healthy middle-aged men. The high degree of intercorrelation amongst several factors makes it difficult to clarify the independent role of any specific factor.

Cross-Sectional Studies↗
PubMed1998

Sphingomyelinase induces aggregation and fusion, but phospholipase A2 only aggregation, of low density lipoprotein (LDL) particles. Two distinct mechanisms leading to increased binding strength of LDL to human aortic proteoglycans.

During atherogenesis, low density lipoprotein (LDL) particles bind to extracellular matrix proteoglycans in the arterial wall, become modified, and appear as aggregated and fused particles. Sphingomyelinase (SMase) and phospholipase A2 (PLA2) have been found in the arterial wall, and, moreover, lesional LDL shows signs of hydrolysis of both sphingomyelin and phosphatidylcholine. We have now studied the effects of these two lipolytic modifications on the aggregation and fusion of LDL particles by hydrolyzing the particles with Bacillus cereus SMase or bee venom PLA2. In addition, the binding strengths of the modified LDL to human aortic proteoglycans (PG) were analyzed on an affinity column. We found that SMase induced aggregation and fusion of LDL, but PLA2 induced only aggregation of the particles. In addition, the SMase-induced aggregation and fusion of LDL was promoted by pretreatment of LDL with PLA2. Determination of the binding strengths of the hydrolyzed LDL revealed that mere lipolysis of LDL without aggregation or fusion, either by SMase or PLA2, did not affect the binding of the particles to PG. Aggregation and fusion of lipolyzed LDL particles, however, increased their strength of binding to PG. Active lysine residues in apolipoprotein B-100 (apoB-100) appear to be involved in the binding of LDL to PG, and, in fact, quantitative 13C NMR analysis revealed that, in the fused LDL particles, the number of active lysine residues per apoB-100 moiety was increased. Moreover, aggregation and fusion of LDL increased the number of apoB-100 copies and, consequently, the number of active lysine residues per aggregate or fused particle. Our present findings therefore (i) show that treatment of LDL with SMase and PLA2 generates modified LDL particles, which then bind to human aortic PG with increased strength, and (ii) suggest that SMase- and PLA2-induced aggregation and fusion of LDL are potential mechanisms leading to focal retention of extracellular lipid in the arterial wall.

Aorta↗
PubMed1998

Ascorbic acid inhibits the increase in low-density lipoprotein (LDL) susceptibility to oxidation and the proportion of electronegative LDL induced by intense aerobic exercise.

BACKGROUND: We have previously reported the finding of an acute increment in the susceptibility of low-density lipoprotein (LDL) to oxidation and in the proportion of electronegative LDL [LDL(-)] after intense exercise. We have now studied the effect of oral supplementation with 1 g ascorbic acid, immediately before a 4-h athletic race, on the susceptibility of LDL to oxidation, the proportion of LDL(-), and the alpha-tocopherol and lipid peroxides content in LDL, in order to inhibit such deleterious changes, and to confirm the oxidative nature of modifications of LDL induced by exercise. METHODS: We studied seven highly trained runners who received a supplement of 1 g ascorbic acid and a control group of seven who did not receive the supplement. The susceptibility of LDL to oxidation was assessed by measurement of conjugated dienes after CuSO4-induced oxidation, the proportion of LDL(-) was determined by anion exchange chromatography, alpha-tocopherol was quantified by reverse-phase high performance liquid chromatography, and lipid peroxides were measured by the thiobarbituric acid-reactive substances (TBARS) method. RESULTS: After exercise, in the control group there was an increase in both the susceptibility of LDL to oxidation (change in lag phase from 51.4 +/- 4.7 min to 47.0 +/- 4.6 min, P < 0.05) and the proportion of LDL(-) (from 11.1 +/- 1.4% to 13.0 +/- 2.2%, P < 0.05), but these did not occur in the ascorbic acid group (change in lag phase from 49.7 +/- 2.3 min to 50.4 +/- 4.2 min, and in LDL(-) from 9.7 +/- 1.7% to 10.1 +/- 1.7%). No significant changes in the absolute amount of LDL alpha-tocopherol were observed after exercise (ascorbic acid group: 6.65 +/- 0.94 mol/mol apoB before the race, 7.13 +/- 0.88 mol/mol apoB after the race; control group: 7.34 +/-0.69 mol/mol apoB before the race, 7.06 +/- 0.69 mol/mol apoB after the race), but significant differences were found when increments or decrements of alpha-tocopherol were tested (alpha-tocopherol increased 9.9 +/- 11.5% in the ascorbic acid group, and decreased 0.6 +/- 7.3% in the control group; P < 0.018). TBARS did not change after exercise. CONCLUSIONS: We conclude that 1 g ascorbic acid inhibits the increase in LDL susceptibility to oxidation after exercise, preventing this acute pro-atherogenic effect. In addition, the observation that LDL(-) enhancement is prevented by ascorbic acid supports the hypothesis that at least some of the circulating LDL(-) originates from oxidative processes.

Adult↗
PubMed1999

Role of plasmalogens in the enhanced resistance of LDL to copper-induced oxidation after LDL apheresis.

Extracorporeal reduction of plasma low density lipoproteins (LDLs) by LDL apheresis was shown to attenuate the proatherogenic influences of LDL, such as impairment of vasodilation and increased monocyte adhesion to the endothelium. In 16 patients with familial hypercholesterolemia, we analyzed whether LDL apheresis by the heparin precipitation procedure affected the oxidative resistance of LDL. Plasma LDL cholesterol concentrations were reduced by 65% after the apheresis. The lag time of copper-mediated LDL oxidation was increased from 103 to 117 minutes (P<0.0005). The LDL contents of alpha-tocopherol and beta-carotene, as well as the ratio of monounsaturated to polyunsaturated fatty acids in LDL, were not altered. However, the LDL apheresis induced a 15% increase in the LDL contents of plasmalogen phospholipids (P<0.0005), a class of ether phospholipids that were recently shown to prevent lipid oxidation. The phosphatidylcholine (PC) to lysoPC ratio was elevated by 16% after the apheresis (P<0.0005). The percent increase in LDL plasmalogen phospholipids showed a close association with the increased lag time after apheresis (P<0.0005). The LDL plasmalogen contents of the blood samples from patients and from normolipidemic donors were also positively related to the lag time (P<0.005). In vitro loading of LDL with plasmalogen phospholipids resulted in a prolongation of the lag time and an increase in the PC/lysoPC ratio. In conclusion, the rapid rise in LDL contents of plasmalogen phospholipids most probably causes the increase in lag time after LDL apheresis. Plasmalogens appear to play an important role in the oxidation resistance of LDL in vivo.

Adult↗