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Effects of Electronegative VLDL on Endothelium Damage in Metabolic Syndrome

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Effects of Electronegative VLDL on Endothelium Damage in Metabolic Syndrome Cardiovascular and Metabolic Risk ORIGINAL ARTICLE Effects of Electronegative VLDL on Endothelium Damage in Metabolic Syndrome 1,2,3,4 1 CHU-HUANG CHEN, MD, PHD JIANWEN DONG, PHD separated VLDL into five subfractions, V1– 1 1 JONATHAN LU, MD MACARTHUR A. ELAYDA, MD, PHD 1 1 V5, on the basis of surface electrical charge SHU-HUA CHEN, BS RICHARD A.F. DIXON, PHD 1 1,2,3,4 rather than particle size. Apart from increa- ROGER Y. HUANG, BS CHAO-YUH YANG, PHD 1,5 ses in the proportion of large VLDL (2), re- H. RAMAZAN YILMAZ, PHD partition of V1–V5 particles with varying degrees of electronegativity may also con- d tribute to changes in VLDL functionality. OBJECTIVE Biochemical heterogeneity governs functional disparities among lipoproteins. We We and others have reported that examined charge-defined VLDL subfractions in metabolic syndrome (MetS) to determine whether their increased electronegativity is associated with increased cytotoxicity and whether high concen- electronegative LDL particles possess ath- trations of highly electronegative subfractions render VLDL harmful to the vascular endothelium. erogenic properties in cultured vascular cells (8–12). Using anion-exchange chro- RESEARCH DESIGN AND METHODSdPlasma VLDL of normal individuals (control matography, we previously resolved subjects) (n = 13) and of those with MetS (n = 13) was resolved into subfractions with increasing plasma LDL into five charge-defined sub- negative charge (V1–V5) by anion-exchange chromatography. Human aortic endothelial cells – – fractions, L1 L5 (8,9). L5, the most nega- were treated with V1 V5 or unfractionated VLDL. tively charged LDL, is the most potent in RESULTSdCompared with the control subjects, individuals with MetS had a significantly higher inducing endothelial cell apoptosis and percentage of V5 VLDL (V5/VLDL%) (34 6 20 vs. 39 6 11%, respectively; P , 0.05) and plasma V5 monocyte–endothelial cell adhesion and concentration ([V5]) (5.5 6 4.4 vs. 15.2 6 8.5 mg/dL, respectively; P , 0.001). Apolipoprotein in inhibiting endothelial progenitor cell (apo)B100 levels decreased and apoC levels increased from V1 to V5, indicating that V5 is apoC-rich differentiation. In addition, L5 is more VLDL. Regression analyses of all 26 individuals showed that [V5] was positively correlated with total abundant in patients with increased car- cholesterol (P = 0.016), triglyceride (P , 0.000001), and V5/VLDL% (P = 0.002). Fasting plasma diac risks (e.g., hypercholesterolemia, P= glucose, but not waist circumference, exhibited a positive trend ( 0.058); plasma HDL cholesterol type 2 diabetes, smoking) than in the exhibited a weak inverse trend (P = 0.138). V5 (10 mg/mL) induced apoptosis in ~50% of endothelial – , healthy population (8,9,13 15). It is un- cells in 24 h. V5 was the most rapidly ( 15 min) internalized subfraction and induced the pro- known whether metabolic abnormalities duction of reactive oxygen species (ROS) in endothelial cells after 20 min. Unfractionated MetS VLDL, but not control VLDL, also induced ROS production and endothelial cell apoptosis. also involve a shift of VLDL particles to a more negative surface electrical charge CONCLUSIONSdIn populations with increased risk of diabetes, the vascular endothelium is and whether such a shift adds to the over- constantly exposed to VLDL that contains a high proportion of V5. The potential impact of V5- all atherogenicity in patients with in- rich VLDL warrants further investigation. creased diabetic risks, including those – with MetS. We hypothesized that V5 is Diabetes Care 35:648 653, 2012 more toxic to vascular endothelial cells than are the other subfractions of VLDL atients with metabolic syndrome ester-rich VLDL, such as b-VLDL, has and that the proportion of V5 in total P (MetS) or type 2 diabetes often have been shown to increase endothelial cell per- VLDL is higher in patients with MetS increased plasma levels of triglycer- meability to LDL (5). Unlike the LDL class than in normal healthy individuals. ides and triglyceride-derived VLDL (1,2). (in which the small, dense particle is consid- Defined by density, the VLDL class (d = ered closely associated with atherosclerosis – RESEARCH DESIGN AND 0.930 1.006 g/mL) contains a heteroge- [6]), large VLDL imparts higher cardiovas- d neous group of lipoprotein particles. Normal cular risk than small VLDL (7). However, METHODS Plasma samples were iso- VLDL particles have been considered non- because the particle size is determined by lated from asymptomatic individuals who toxic to vascular cells, but apolipoprotein nuclear magnetic resonance, isolating large did (MetS subjects) or did not (control (apo)CIII-rich VLDL exhibits atherogenicity VLDL for chemical and functional charac- subjects) meet the criteria for MetS accord- – fi ing to the National Cholesterol Education by enhancing monocyte endothelial cell terization is technically dif cult. Using – adhesion (3,4). Historically, cholesteryl anion-exchange chromatography, we have Program Adult Treatment Panel III guide- lines (16). All participants gave informed ccccccccccccccccccccccccccccccccccccccccccccccccc consent for the use of their plasma; the study was conducted according to the prin- From the 1Texas Heart Institute, Houston, Texas; 2Baylor College of Medicine, Houston, Texas; 3China Medical University, Taichung, Taiwan; 4China Medical University Hospital, Taichung, Taiwan; and the ciples in the Declaration of Helsinki. Total 5Department of Medical Biology, Mevlana University Faculty of Medicine, Konya, Turkey. VLDL and LDL (d = 1.019–1.063 g/mL) Corresponding author: Chu-Huang Chen, [email protected]. were isolated by sequential ultracentrifuga- Received 23 August 2011 and accepted 18 November 2011. tion (8). VLDL and LDL samples were re- DOI: 10.2337/dc11-1623 – – © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly solved into V1 V5 and L1 L5 subfractions cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ by anion-exchange chromatography. In licenses/by-nc-nd/3.0/ for details. brief, the lipoprotein samples were injected 648 DIABETES CARE, VOLUME 35, MARCH 2012 care.diabetesjournals.org Chen and Associates through a UnoQ12 column (BioRad, (ROS) after 20 min of exposure to the apoptosis (30%) after 24 h (Fig. 1E). How- Hercules, CA) that had been equilibrated VLDL subfractions with the use of a total ever, VLDL and LDL from MetS subjects with buffer A (0.02 mol/L Tris-HCl, pH ROS detection kit (Enzo, New York, differed in that V5 was more cytotoxic 8.0, containing 1 mmol/L EDTA). Subfrac- NY). than L5 at lower (10 mg/mL) and higher tions were eluted by use of a multistep gra- (50 mg/mL) concentrations and that V3 dient of buffer B (1 mol/L NaCl in buffer A). RESULTSdTable 1, with the demo- and V4 were also cytotoxic (although Samples equilibrated with buffer A were graphic and lipid profiles, shows that the to a lesser degree than V5) compared eluted by using a linear gradient program control and MetS groups differed signif- with the relatively benign L1–L4. at a flow rate of 2 mL/min. Effluent was icantly in age, fasting plasma glucose To examine the relationship between monitored at 280 nm and protected from (FPG), total cholesterol, triglycerides, [V5] and the components of MetS criteria ex vivo oxidation with 5 mmol/L EDTA; VLDL cholesterol, BMI, and waist circum- (i.e., FPG, waist circumference, HDL cho- protein concentrations were determined ference. Anion-exchange chromatography lesterol, and triglyceride), total cholesterol, by the Lowry method (8). Paired Student of VLDL samples showed that the distribu- and V5/VLDL, we performed linear regres- t tests were used to compare the percentage tion of the five subfractions, V1–V5, was sion analysis of the combined groups (MetS of V5 VLDL (V5/VLDL%) and plasma V5 shifted toward the most negatively charged and control; n = 26). A positive, though concentrations ([V5]) between the control subfractions (i.e., V5) more in the MetS nonsignificant, trend was observed be- and MetS groups. Linear regression ana- group than in the control group (Fig. 1A). tween FPG and [V5] (Fig. 2). We did not lyses with a 95% CI were used to examine In group analyses, V5/VLDL% was signifi- see a forward, inverse relationship between the correlation between demographic/ cantly increased in the MetS vs. control [V5] and either enlarged waist circumfer- blood parameters and [V5] in the combined group (39 6 11 vs. 34 6 20%, respectively; ence or reduced HDL cholesterol levels, al- control and MetS cohorts (n = 26). Data are P , 0.05) (Fig. 1B). Moreover, the plasma though both are components of the MetS expressed as means 6 SD. The normality of concentration of V5 was 2.8-fold higher in criteria (Fig. 2). As expected, [V5] elevation the data was verified with the Kolgomorov- the MetS group than in the control group was closely correlated with increases in Smirnov test. A P value of ,0.05 was con- (15.2 6 8.5 vs. 5.5 6 4.4 mg/dL, respec- both V5/VLDL% (R = 0.584; P = 0.002) sidered significant. tively; P , 0.001) (Fig. 1C). For each unit and plasma triglyceride concentration To evaluate whether the VLDL sub- amount of total protein in the MetS sam- (R =0.82;P , 0.000001) (Fig. 2). Probably fractions vary in protein content, V1–V5 ples, the relative content of apoB100 pro- attributable to the contribution of the tri- were analyzed by electrophoresis in 0.7% gressively decreased in the direction of V1 glyceride component in total cholesterol, agarose (50 mmol/L sodium barbital, pH to V5, whereas that of apoE and apoC pro- [V5] elevation was also correlated with in- 8.4). For SDS-PAGE, the subfractions gressively increased (Fig. 1D). In vitro stud- creased total cholesterol levels (R =0.469; were delipidated, solubilized, and sepa- ies showed that even at low concentrations P = 0.016) (Fig.
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