Abstract-Mean plasma phospholipid transfer protein (PLTP) concentrations were measured for the first time by using a competitive enzyme-linked immunosorbent assay. PLTP mass levels and phospholipid transfer activity values, which were significantly correlated among normolipidemic plasma samples (rϭ0.787, PϽ0.0001), did not differ between normolipidemic subjects (3.95Ϯ1.04 mg/L and 575Ϯ81 nmol ⅐ mL Ϫ1 ⅐ h Ϫ1 , respectively; nϭ30), type IIa hyperlipidemic patients (4.06Ϯ0.84 mg/L and 571Ϯ43 nmol ⅐ mL Ϫ1 ⅐ h Ϫ1 , respectively; nϭ36), and type IIb hyperlipidemic patients (3.90Ϯ0.79 mg/L and 575Ϯ48 nmol ⅐ mL Ϫ1 ⅐ h Ϫ1 , respectively; nϭ33). No significant correlations with plasma lipid parameters were observed among the various study groups. In contrast, plasma concentrations of the related cholesteryl ester transfer protein (CETP) were higher in type IIa and type IIb patients than in normolipidemic controls, and significant, positive correlations with total and low density lipoprotein cholesterol levels were noted. Interestingly, plasma PLTP mass concentration and plasma phospholipid transfer activity were significantly higher in patients with non-insulin-dependent diabetes mellitus (nϭ50) than in normolipidemic controls (6.76Ϯ1.93 versus 3.95Ϯ1.04 mg/L, PϽ0.0001; and 685Ϯ75 versus 575Ϯ81 nmol ⅐ mL, PϽ0.0001, respectively). In contrast, CETP levels did not differ significantly between the 2 groups. Among non-insulin-dependent diabetes mellitus patients, PLTP levels were positively correlated with fasting glycemia and glycohemoglobin levels (rϭ0.341, Pϭ0.0220; and rϭ0.382, Pϭ0.0097, respectively) but not with plasma lipid parameters. It is proposed that plasma PLTP mass levels are related to glucose metabolism rather than to lipid metabolism. Key Words: cholesteryl ester transfer protein Ⅲ lipid transfer Ⅲ ELISA Ⅲ glucose Ⅲ non-insulin-dependent diabetes mellitus I n vivo, plasma lipoproteins do not constitute stable entities but are continuously remodeled through the action of several enzymes and lipid transfer proteins. In particular, cholesteryl ester transfer protein (CETP) 1 and phospholipid transfer protein (PLTP), 2 related proteins belonging to the lipid transfer/lipopolysaccharide binding protein (LT/LBP) family, 1 can promote the exchange of lipid species between various plasma lipoprotein fractions. In fact, studies over the past few years have demonstrated that both CETP and PLTP produce multiple effects on lipoprotein structure and composition. Thus, CETP promotes the exchange of neutral lipids, ie, CEs and triglycerides, between plasma lipoprotein fractions, leading to alterations in both the neutral lipid content and the size distribution of lipoproteins. 2,3 PLTP can facilitate the transfer of phospholipids between lipoprotein particles, 4 and it was lately shown to transfer lipopolysaccharides, 5 unesterified cholesterol, 6 and ␣-tocopherol 7 as well. In addition, PLTP constitutes an important determinant of the size distribution of HDL. 3,8 -12 Taken together, recent advances have raised considerab...
Aims/hypothesis: In healthy normolipidaemic and normoglycaemic control subjects, HDL are able to reverse the inhibition of vasodilation that is induced by oxidised LDL. In type 2 diabetic patients, HDL are glycated and more triglyceride-rich than in control subjects. These alterations are likely to modify the capacity of HDL to reverse the inhibition of vasodilation induced by oxidised LDL. Subjects and methods: Using rabbit aorta rings, we compared the ability of HDL from 16 type 2 diabetic patients and 13 control subjects to suppress the inhibition of vasodilation that is induced by oxidised LDL. Results: Oxidised LDL inhibited endothelium-dependent vasodilation (maximal relaxation [Emax]=58.2± 14.6 vs 99.3±5.2% for incubation without any lipoprotein, p<0.0001). HDL from control subjects significantly reduced the inhibitory effect of oxidised LDL on vasodilatation (Emax=77.6±12.9 vs 59.5±7.7%, p<0.001), whereas HDL from type 2 diabetic patients had no effect (Emax=52.4±20.4 vs 57.2±18.7%, NS). HDL triglyceride content was significantly higher in type 2 diabetic patients than in control subjects (5.3±2.2 vs 3.1±1.4%, p<0.01) and was highly inversely correlated to Emax for oxidised LDL+HDL in type 2 diabetic patients (r=−0.71, p<0.005). Conclusions/interpretation: In type 2 diabetes mellitus, the ability of HDL to counteract the inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL is impaired and is inversely correlated with HDL triglyceride content. These findings suggest that HDL are less atheroprotective in type 2 diabetic patients than in control subjects.
Cholesterol derivatives in oxidized LDL can reduce maximal arterial relaxation through a specific effect on vascular endothelial cells.
Aims/hypothesis In healthy individuals, HDL can counteract the inhibition of vasorelaxation induced by oxidised LDL. Several abnormalities such as increased size, glycation and decreased paraoxonase activity have been reported for HDL from type 1 diabetic patients. Thus, we hypothesised that the ability of HDL to protect vessels against impairments of vasorelaxation would be decreased in these patients. Methods We compared the ability of HDL from 18 type 1 diabetic patients and 12 control participants to counteract the inhibition of endothelium-dependent relaxation induced by oxidised LDL on rabbit aorta rings. Results Serum triacylglycerol and total cholesterol, LDLand HDL-cholesterol were similar in type 1 diabetic and control participants. Fasting glycaemia and the HDLfructosamine level were higher in diabetic patients than in controls (9.06±3.55 vs 5.27±0.23 mmol/l, p<0.005; and 10.2±3.2 vs 7.7±2.5 μmol/g protein, p<0.05, respectively). HDL composition, size and paraoxonase activity were similar in both groups. HDL from controls reduced the inhibitory effect of oxidised LDL on maximal relaxation (E max ; 79.3± 11.8 vs 66.4±11.7%, p<0.05), whereas HDL from type 1 diabetic patients had no effect (E max =70.6±17.4 vs 63.9± 17.2%, NS). In type 1 diabetic patients, E max was not correlated with glycaemia or the HDL-fructosamine level. Conclusions/interpretation HDL particles from type 1 diabetic patients do not protect against inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL, in contrast to HDL particles from healthy individuals. This defect cannot be explained by abnormalities in HDL composition, size or paraoxonase activity, and may contribute to the early development of atherosclerotic lesions in type 1 diabetic patients.
The functional heterogeneity of HDL is attributed to its diverse bioactive components. We evaluated whether the vasodilatory effects of HDL differed across HDL subpopulations, reflecting their distinct molecular composition. The capacity of five major HDL subfractions to counteract the inhibitory effects of oxidized LDL on acetylcholine-induced vasodilation was tested in a rabbit aortic rings model. NO production, an essential pathway in endothelium-dependent vasorelaxation, was studied in simian vacuolating virus 40-transformed murine endothelial cells (SVECs). Small dense HDL3 subfractions displayed potent vasorelaxing activity (up to +31% vs. baseline, < 0.05); in contrast, large light HDL2 did not induce aortic-ring relaxation when compared on a total protein basis. HDL3 particles were enriched with sphingosine-1-phosphate (S1P) (up to 3-fold vs. HDL2), with the highest content in HDL3b and -3c that concomitantly revealed the strongest vasorelaxing properties. NO generation was enhanced by HDL3c in SVECs (1.5-fold, < 0.01), a phenomenon that was blocked by the S1P receptor antagonist, VPC 23019. S1P-enriched reconstituted HDL (rHDL) was a 1.8-fold ( < 0.01) more potent vasorelaxant than control rHDL in aortic rings. Small dense HDL3 particles displayed potent protective effects against oxidative stress-associated endothelium dysfunction, potentially reflecting their elevated content of S1P that might facilitate interaction with S1P receptors and ensuing NO generation.
Abdominal obesity is associated with a decreased plasma concentration of HDL cholesterol and with qualitative modifications of HDL, such as triglyceride enrichment. Our aim was to determine, in isolated aorta rings, whether HDL from obese subjects can counteract the inhibitory effect of oxidized low density lipoprotein (OxLDL) on endothelium-dependent vasodilation as efficiently as HDL from normolipidemic, lean subjects. Plasma triglycerides were 74% higher (P , 0.005) in obese subjects compared with controls, and apolipoprotein A-I (apoA-I) and HDL cholesterol concentrations were 12% and 17% lower (P , 0.05), respectively. HDL from control subjects significantly reduced the inhibitory effect of OxLDL on vasodilation [maximal relaxation (E max ) 5 82.1 6 8.6% vs. 54.1 6 8.1%; P , 0.0001], but HDL from obese subjects had no effect (E max 5 47.2 6 12.5% vs. 54.1 6 8.1%; NS). In HDL from abdominally obese subjects compared with HDL from controls, the apoA-I content was 12% lower (P , 0.05) and the triglyceride-to-cholesteryl ester ratio was 36% higher (P 5 0.08)). E max (OxLDL 1 HDL) was correlated with HDL apoA-I content and triglyceride-to-cholesteryl ester ratio (r 5 0.36 and r 5 20.38, respectively; P , 0.05). We conclude that in abdominally obese subjects, the ability of HDL to counteract the inhibitory effect of OxLDL on vascular relaxation is impaired. This could contribute to the increased cardiovascular risk observed in these subjects.-Perségol, L., B. Vergès, P. Gambert, and L. Duvillard. Inability of HDL from abdominally obese subjects to counteract the inhibitory effect of oxidized LDL on vasorelaxation. Abdominal obesity and insulin resistance have been shown to be associated with an increased cardiovascular risk (1-3). Several atherogenic abnormalities are commonly observed in abdominally obese subjects, such as hypertriglyceridemia, decreased HDL cholesterol concentration, hypertension, and increased oxidative stress or oxidized low density lipoprotein (OxLDL) concentration (4-6).HDL particles have multiple antiatherosclerosis properties. Among them is the beneficial effect they exert on endothelium-dependent vasorelaxation. Indeed, HDL particles can counteract the inhibitory effect of OxLDL on endothelium-dependent vasodilation in isolated rabbit aorta rings (7). Moreover, the intravenous administration of reconstituted HDL either to hypercholesterolemic men or to ATP binding cassette A1-deficient heterozygotes, both with an initially impaired endothelium-dependent vasorelaxation, restored a normal vasorelaxation in these subjects (8,9).Endothelium dysfunction, a predictor for cardiovascular events, has been observed in overweight patients with visceral obesity and was demonstrated to be associated with body fat distribution (10-12). Because of qualitative modifications, HDL from these subjects may be less protective against impairments of endothelium-dependent vasorelaxation than HDL from lean normolipidemic subjects. Therefore, the purpose of our study was to determine whether or not HDL ...
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