Junjun Wang

Native, oxidized lipoprotein(a) and lipoprotein(a) immune complex in patients with active and inactive rheumatoid arthritis: Plasma concentrations and relationship to inflammation

BACKGROUNDnSeveral studies suggest that lipoprotein (a) [Lp(a)] act as acute phase reactant and be associated with early atherosclerosis in rheumatoid arthritis (RA). Oxidized Lp(a) [ox-Lp(a)] and Lp(a) immune complex (IC) concentrations both increased in patients with coronary heart disease. We investigated Lp(a), ox-Lp(a) and Lp(a)-IC concentrations in RA patients and to explore the relationships with inflammatory disease activity markers.nnnMETHODSnPlasma Lp(a), ox-Lp(a) and Lp(a)-IC concentrations, and inflammatory markers were analyzed in 54 patients with RA, including 23 active and 21 inactive RA, and 60 control subjects.nnnRESULTSnLp(a) and ox-Lp(a) concentrations in active RA were higher than those in both inactive RA and control; Lp(a)-IC concentrations in active RA were also higher than inactive RA, while no difference was found in Lp(a), ox-Lp(a) and Lp(a)-IC concentrations between inactive RA and control. Lp(a) concentrations were found positively correlated with ox-Lp(a) and Lp(a)-IC concentrations, respectively; ox-Lp(a) concentrations were also related with Lp(a)-IC. Lp(a), ox-Lp(a) and Lp(a)-IC were all found positively related with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), respectively.nnnCONCLUSIONSnNative, oxidized Lp(a) and Lp(a)-IC concentrations increased in active RA patients. Inflammation may induce the changes of Lp(a), resulting in increased ox-Lp(a) and Lp(a)-IC, and may play an important role in atherosclerosis.

Detection of IgG-bound lipoprotein(a) immune complexes in patients with coronary heart disease

BACKGROUNDnLDL-immune complexes (IC) have a powerful pathogenic role for inducing foam cell formation in vitro more efficiently than any other known mechanism. Studies have also shown that plasma LDL-IC concentration is a powerful marker for the development of atherosclerosis. The structure, fatty acid composition and antioxidant concentrations of Lp(a) and LDL are quite similar. The same oxidation pattern has also been described for both lipoproteins. Modified forms of Lp(a), some resembling oxidized Lp(a), have been identified in human atheromatous lesions. The existence of autoantibodies against MDA-Lp(a) in vivo is also presented. Therefore, we suppose that Lp(a) might trigger an immune response leading to the production of autoantibodies and subsequently to the formation of immune complexes. This study examined the existence of IgG-bound Lp(a)-IC and investigated its value as a risk factor for the development of atherosclerosis.nnnMETHODSnWe developed two sandwich ELISAs for measuring plasma Lp(a)-IC and LDL-IC concentrations, using anti-human IgG(Fab) as the capture antibody, and quantitating with monoclonal anti-apo(a) or anti-apoB enzyme conjugate. Their concentrations were studied in 160 patients with coronary heart disease (CHD) and 290 control subjects.nnnRESULTSnPlasma TC, LDL-C, TG and apoB concentrations in CHD patients were all significantly increased, whereas HDL-C and apoAI concentrations were decreased. The Lp(a) concentrations in the patients with CHD were also significantly different from those of control (262.4+/-220.0 vs. 211.3+/-199.4 mg/l, P<0.005). Plasma Lp(a)-IC (2.24+/-1.71 vs. 1.62+/-1.50 AU, P<0.0001) and LDL-IC (2.77+/-1.29 vs. 1.40+/-0.92 AU, P<0.0001) concentrations in patients with CHD were both significantly higher than those of control. The relationships between Lp(a)-IC, LDL-IC concentrations and other lipid traits in all the studied subjects (n=450) were carried out. LDL-IC concentrations were positively correlated with LDL-C, apoB, TC, TG and Lp(a) concentrations, while negatively correlated with HDL-C and apoAI concentrations, respectively. Similarly, Lp(a)-IC concentrations were positively correlated with Lp(a), LDL-C, apoB and TC concentrations, while negatively correlated with HDL-C and apoAI concentrations, respectively. Furthermore, a significantly positive relation between LDL-IC and Lp(a)-IC concentrations was also found (r=0.313, P<0.0001).nnnCONCLUSIONSnWe report the existence of Lp(a)-IC in both the plasma of patients with CHD and control subjects. Lp(a)-IC concentration increases in the CHD patients.

CETP gene mutation (D442G) increases low-density lipoprotein particle size in patients with coronary heart disease

BACKGROUNDnSmall, dense low-density lipoprotein (LDL) in subjects with the atherogenic pattern B has been established as a risk factor of atherosclerosis. Cholesteryl ester transfer protein (CETP) plays an important role in the transfer and exchange of cholesteryl esters and triglycerides between the lipoprotein classes of human plasma. It has been shown that CETP can also change the particle size of high-density lipoprotein (HDL) and LDL subfractions in vitro. Previous clinical studies about CETP gene mutations mainly focused on abnormalities in HDL, few involved those in LDL.nnnOBJECTIVESnTo investigate the effect of the D442G mutation in the CETP gene on major peak size of LDL particles in patients with coronary heart diseases (CHD).nnnMETHODSnD442G mutation in the CETP gene was detected using the PCR-RFLP. LDL particles sizes were analyzed by 2-16% nondenaturing polyacrylamide gradient gels in CHD patients with D442G mutation in the CETP gene.nnnRESULTSnSix heterozygotes and one homozygote were found to have the D442G mutation among 200 CHD patients. The frequency of this mutation was 3.5%. The major peak size of LDL in patients with gene mutation (n=7) was significantly larger than that in patients without the mutation (n=40) (26.92 +/- 0.79 nm vs. 25.71 +/- 0.66 nm, respectively; P<0.01). All the patients with the gene mutation expressed pattern A, whereas only about half of the patients without the mutation expressed this pattern. The patients with gene mutation had decreased plasma CETP concentration, while increased concentration of HDL-C and apolipoprotein A-I compared with controls.nnnCONCLUSIONSnCETP gene mutation (D442G) increases LDL particle size. This suggests that CETP play an antiatherogenic role.

Serum cholesteryl ester transfer protein concentrations in healthy Chinese subjects and cardio–cerebrovascular disease patients

Serum cholesteryl ester transfer protein (CETP) concentration was measured in 1128 healthy Chinese subjects using a sandwich enzyme immunoassay and was 1.84 +/- 1.55 mg/l (mean +/- S.D.). The frequency distribution of CETP in healthy subjects was markedly skewed towards low concentrations. The CETP concentration in females was significantly higher than that in males (2.40 +/- 1.65 mg/l vs. 1.49 +/- 1.37 mg/l, P < 0.001). There was a weak inverse correlation between the CETP concentration and age (r = -0.19, P < 0.001). The CETP concentrations were significantly higher in 117 myocardial infarction (MI) survivors and 110 stroke patients than that in 335 healthy, age-matched males (1.98 +/- 1.68 173 +/- 1.45, and 1.40 +/- 1.37 mg/l respectively, P < 0.01), while no relation was found between CETP concentration and lipids concentration in MI, stroke and healthy group.

Inhibitory effects of rosa roxburghii tratt juice on in vitro oxidative modification of low density lipoprotein and on the macrophage growth and cellular cholesteryl ester accumulation induced by oxidized low density lipoprotein.

BACKGROUNDnRosa roxburghii tratt juice (RRTJ) administration has been shown to significantly ameliorate atherosclerotic diseases in cholesterol-fed animals. However, the mechanism for the antiatherogenic effect of RRTJ is not clear.nnnMETHODSnWe investigated the effects of RRTJ on in vitro oxidative modification of LDL and on LDL-induced macrophage growth and cellular cholesteryl ester (CE) accumulation. The effects of RRTJ on LDL oxidative modification were assessed by relative electrophoretic migration, thiobarbituric acid-reactive substance (TBARS) content, and the formation of conjugated dienes. The inhibition of RRTJ on oxidized LDL (Ox-LDL)-induced murine peritoneal macrophage growth was evaluated by a cell-counting assay and an MTT assay. The effect of RRTJ on Ox-LDL-induced cellular CE accumulation was examined after macrophages were incubated with Ox-LDL in the presence of RRTJ. To clarify the mechanism of the inhibitory effect of RRTJ on Ox-LDL-induced CE accumulation in macrophages, its capacity for cholesterol efflux from macrophage-derived foam cells were examined.nnnRESULTSnWe showed that RRTJ significantly reduced LDL oxidative susceptibility. In addition, RRTJ effectively suppressed Ox-LDL-induced macrophage growth and especially Ox-LDL-induced CE accumulation in murine peritoneal macrophages by promoting cellular cholesterol efflux.nnnCONCLUSIONnThese results indicated that RRTJ exerted its antiatherogenic effects largely due to its ability to inhibit the oxidative modification of LDL and to suppress the formation of foam cells.

Detection of serum β2-GPI–Lp(a) complexes in patients with systemic lupus erythematosus

BACKGROUNDnCirculating beta(2)-glycoprotein-I-oxidized low-density lipoprotein (beta(2)-GPI-ox-LDL) complexes have been found in patients with systemic lupus erythematosus (SLE) and other autoimmune diseases as a contributor to the development of autoimmune-mediated atherosclerosis. In vitro study showed that beta(2)-GPI also bound with high affinity to atherogenic lipoprotein (a) [Lp(a)] which shares structural similarity to LDL. We examined the existence and clinical significance of serum complexes of beta(2)-GPI with Lp(a) in SLE patients.nnnMETHODSnA sandwich ELISA was developed for measuring serum concentrations of beta(2)-GPI-Lp(a) complexes, using rabbit anti-human beta(2)-GPI antibody as capturing antibody, and quantitating with antibody against apo(a). Forty-seven SLE patients and 42 healthy controls were studied.nnnRESULTSnBoth Lp(a) (400+/-213 mg/l vs. 181+/-70 mg/l) and ox-Lp(a) (27.07+/-22.30 mg/l vs. 8.20+/-4.55 mg/l) concentrations were higher in SLE patients than in controls (P<0.0001). beta(2)-GPI-Lp(a) complexes were detectable in both controls and SLE. The complexes levels in SLE were higher than in controls (0.96+/-0.41 U/ml vs. 0.59+/-0.20 U/ml, P<0.0001) and was positively correlated with ox-Lp(a) (P<0.001).nnnCONCLUSIONSnWe report the existence of beta(2)-GPI-Lp(a) complexes in both controls and SLE patients. The complexes levels increase in SLE.

Elevated concentrations of oxidized lipoprotein(a) are associated with the presence and severity of acute coronary syndromes

OBJECTIVEnTo investigate possible mechanisms and association of increased oxidized Lp(a) [ox-Lp(a)] levels with presence and extent of acute coronary syndromes (ACS).nnnMETHODSnOx-Lp(a) levels were studied in 96 patients with ACS, 89 patients with stable coronary artery disease (CAD), and 100 control subjects.nnnRESULTSnCompared to control, ox-Lp(a) levels increased in stable CAD patients (P<0.001), and especially in ACS (P<0.001) (ACS, 16.29+/-13.80 microg/ml; stable CAD, 10.04+/-10.32 microg/ml; control, 7.10+/-9.16 microg/ml). The ratio of ox-Lp(a) to Lp(a) was higher in the ACS than those in the stable CAD (P<0.05) and control (P<0.001). Ox-Lp(a) levels were found associated with a graded increase in extent of angiographically documented CAD in the ACS (R=0.275, P=0.007), while not in the stable CAD (R=0.090, P=0.402). Multiple linear regression analysis found ox-Lp(a) (beta=0.271, P=0.019), age (beta=0.244, P=0.038) and TG (beta=0.213, P=0.070) accounted for 11.1% of the variation in the extent of angiographically documented CAD in ACS patients; Lp(a) (beta=0.415, P=0.000) and extent of CAD (beta=0.193, P=0.071) accounted for 21.5% of that in ox-Lp(a) levels.nnnCONCLUSIONnElevated ox-Lp(a) levels are associated with presence and severity of ACS, and may be useful for identification of patients with ACS.

Measurement of oxidized lipoprotein (a) in patients with acute coronary syndromes and stable coronary artery disease by 2 ELISAs: Using different capture antibody against oxidized lipoprotein (a) or oxidized LDL

OBJECTIVEnTo evaluate clinical value of oxidized lipoprotein(a) [ox-Lp(a)] levels.nnnDESIGN AND METHODSnOx-Lp(a) were measured by 2 ELISAs using antibodies against ox-Lp(a) [ox-Lp(a)1] or oxidized low-density lipoprotein [ox-Lp(a)2], and studied in 161 acute coronary syndromes (ACS) patients, 114 stable coronary artery disease (CAD) and 100 control subjects.nnnRESULTSnOx-Lp(a)1 was found related with ox-Lp(a)2 (r=0.864, P=0.000). Controlling for plasma lipids, Lp(a) and clinical characteristics, odds ratios of ox-Lp(a)1 on ACS and stable CAD were 5.06 (95% confidence interval 1.82-14.04) and 2.20 (0.78-6.22); those of ox-Lp(a)2 were 3.37 (1.07-10.63) and 1.35 (0.41-4.48), respectively. Receiver-operating characteristic curve analysis confirmed that performances of ox-Lp(a)1 were significantly superior to those for ox-Lp(a)2 in ACS (area: 0.803 vs. 0.723, P<0.001) and stable CAD (area: 0.670 vs. 0.607, P<0.01).nnnCONCLUSIONnOx-Lp(a) levels using antibodies against ox-Lp(a) may represent a better risk marker than those using antibodies against oxidized low-density lipoprotein for ACS and stable CAD.

The level of malondialdehyde-modified LDL and LDL immune complexes in patients with rheumatoid arthritis

OBJECTIVESnTo explore possible associations of malondialdehyde-modified low-density lipoprotein (MDA-LDL) and LDL-immune complexes (LDL-IC) with atherosclerosis in rheumatoid arthritis (RA).nnnDESIGN AND METHODSnPlasma MDA-LDL, LDL-IC levels and mechanisms of the changes were investigated in RA patients with or without coronary artery disease (CAD), simple CAD patients and control.nnnRESULTSnMDA-LDL and LDL-IC levels were found increased in all the studied patients, the RA patients with CAD exhibited the most significant changes. MDA-LDL levels were higher in the RA patients with CAD than those both in the simple RA and CAD patients. Multiple linear regression analysis showed that CAD, LDL-IC and erythrocyte sedimentation rate accounted for 36.5% of the variation in MDA-LDL levels; and age, activity, MDA-LDL and rheumatoid factors accounted for 34.5% of the variation in LDL-IC.nnnCONCLUSIONSnHigh levels of MDA-LDL and LDL-IC are risk factors for increased risk of atherosclerosis in RA patients and are associated with inflammation.

Plasma oxidized lipoprotein(a) and its immune complexes are present in newborns and children

BACKGROUNDnOxidized Lp(a) [ox-Lp(a)] has been reported to play more potent roles than native Lp(a) in atherosclerosis. We investigated the distribution characteristics of plasma ox-Lp(a) and Lp(a) immune complex [Lp(a)-IC] levels in newborns and children.nnnMETHODSnPlasma ox-Lp(a) and Lp(a)-IC levels were measured in 747 children and 30 cord blood by ELISAs.nnnRESULTSnThe mean levels of Lp(a), ox-Lp(a) and Lp(a)-IC were much lower in newborns than in children (P<0.001), and increased rapidly to that in children after birth. The distributions of Lp(a), ox-Lp(a) and Lp(a)-IC were skewed toward low values in children, no difference of their levels was found in each of the 13year groups. The levels of ox-Lp(a) correlated positively with total and LDL cholesterol, Lp(a) and Lp(a)-IC; Lp(a)-IC correlated positively with sex, total and LDL cholesterol, Lp(a) and ox-Lp(a), respectively. Multiple linear regression analysis showed Lp(a) and Lp(a)-IC accounted for 42% of the variation in ox-Lp(a) levels, and ox-Lp(a) accounted for 30% of that in Lp(a)-IC.nnnCONCLUSIONSnThe fact that ox-Lp(a) and Lp(a)-IC are present in newborns and children suggests that oxidized lipoproteins play an initiating role in atherosclerotic process.