Thioredoxin reductase 1 is upregulated in atherosclerotic plaques: specific induction of the promoter in human macrophages by oxidized low-density lipoproteins.

Uptake of modified low-density lipoproteins (LDLs) by macrophages in the arterial wall is an important event in atherogenesis. Indeed, oxidatively modified LDLs (oxLDLs) are known to affect various cellular processes by modulating oxidation-sensitive signaling pathways. Here we found that the ubiquitous 55 kDa selenoprotein thioredoxin reductase 1 (TrxR1), which is a key enzyme for cellular redox control and antioxidant defense, was upregulated in human atherosclerotic plaques and expressed in foam cells. Using reverse transcription polymerase chain reaction analysis, we also found that oxLDLs, but not native LDLs (nLDLs), dose-dependently increased TrxR1 mRNA in human monocyte-derived macrophages (HMDMs). This stimulating effect was specific for oxLDLs, as pro-inflammatory factors, such as lipopolysaccharides (LPSs), interleukin-1beta (IL-1beta), interleukin-6 (Il-6), and tumor necrosis factor alpha (TNFalpha), under the same conditions, failed to induce TrxR1 mRNA levels to the same extent. Moreover, phorbol ester-differentiated THP-1 cells or HMDMs transiently transfected with TrxR1 promoter fragments linked to a luciferase reporter gene allowed identification of a defined promoter region as specifically responding to the phospholipid component of oxLDLs (p <.05 vs. phospholipid component of nLDLs). Gel mobility shift analyses identified a short 40-nucleotide stretch of the promoter carrying AP-1 and HoxA5 consensus motifs that responded with an altered shift pattern in THP-1 cells treated with oxLDLs, however, without evident involvement of either the Fos, Jun, Nrf2 or HoxA5 transcription factors.

High serum apolipoprotein AIV levels in renal transplant recipients.

BACKGROUND: Human apolipoprotein (apo) AIV might play a role in post-transplant reverse cholesterol transport, which appears to be comparable to that seen in healthy subjects. However, there may be subtle differences between healthy individuals and renal transplant recipients, given the other abnormalities of lipoprotein metabolism in the latter. Therefore, the aim of the present study was to investigate possible changes of serum apo AIV levels in renal transplant recipients, and to evaluate potential factors influencing these levels. PATIENTS AND METHODS: Total and free serum apo AIV was determined in 36 clinically stable renal transplant recipients and in 20 sex- and age-matched healthy control subjects. RESULTS: Mean total serum apo IV concentrations (+/- SD) were significantly higher in renal transplant recipients than in control subjects (202 +/- 102 vs 79 +/- 45 mg/l, p < 0.01). The percentage of lipoprotein-free fractions of apo AIV was comparable in both groups. The elevated total serum concentrations of apo AIV were mainly related to creatinine clearance and partially to serum triglyceride levels in renal transplant recipients. CONCLUSION: Our data suggest that the observed elevation of serum apo AIV concentrations in renal transplant recipients is essentially related to the presence of impaired renal function.

Evolution pattern of auto-antibodies against oxidized low-density lipoproteins in renal transplant recipients.

An increased degree of oxidative stress in renal transplant recipients and a possible role of ciclosporin A (Cs-A) immunosuppressive therapy in this process have already been described. However, prospective data using in vivo markers and the influence of Cs-A in the oxidizability of low-density lipoprotein (LDL) are scarce. We aimed at investigating in this prospective study the evolution pattern of auto-antibodies directed against malondialdehyde-modified LDL (MDA-LDL) and Cu2+-oxidized LDL in 28 stable renal transplant recipients on Cs-A immunosuppressive therapy before and after 3 successive years of renal transplantation. Also, the effect of enrichment of LDL with Cs-A on the susceptibility of LDL to in vitro oxidation was tested. The results showed a significant increase of both auto-antibody titres (MDA-LDL and Cu2+-oxidized LDL) after 1 year, and the values remained high during the 2nd and the 3rd year following transplantation. The yearly mean relative variations of auto-antibodies against MDA-LDL and Cu2+-oxidized LDL during the follow-up period were 133, 149, and 137%, and 111, 115, and 117%, respectively. A significant correlation was observed during the 1st year between Cs-A trough blood level and Cu2+-oxidized LDL auto-antibody: r = 0.04 (p = 0.046). Incorporation of Cs-A into LDL from healthy volunteers showed no changes during the lag phase in comparison with Cs-A-free LDL, indicating that Cs-A had no effect on in vitro LDL oxidizability. Our results suggest that Cs-A may be involved earlier in the LDL oxidation, but the mechanism by which it acts is still unclear.

Apolipoprotein AI and apolipoprotein B containing particle analysis in normolipidemic hemodialyzed patients: evidence of free apolipoprotein E.

Whole plasma from 6 normolipidemic chronic renal failure (CRF) patients undergoing hemodialysis treatment was passed through the anti-apolipoprotein (Apo) AI immunosorbent column connected to the anti-Apo B immunoaffinity column. Apo AI and B containing particles were analyzed for lipid and Apo contents. The results were compared with findings obtained in age-matched normolipidemic healthy controls. Although plasma Apo AI and AII levels decreased in CRF patients, the concentrations of Apo CII, CIII, and E coeluted with Apo AI were similar to those of the controls. The slightly elevated plasma concentrations of Apo CII and CIII in the CRF patients studied were shown to be associated with Apo B containing particles. The nonretained fraction from both groups contains no Apo AI and no Apo B, but still contains lipids and other Apo such as Apo AII and Apo CII. The occurrence of approximately 29% of plasma Apo E in this fraction constitutes the main abnormality found in these patients (< 5% in controls). A two-phase electroimmunoassay shows that this Apo E did not correspond to the plasma E-AII complex. These findings show that the compositional alterations of Apo AI and Apo B containing particles in CRF patients were observed even in normolipidemic patients and suggest that the kidney may play a metabolic role in the removal of free forms of lipoprotein particles such as free Apo E.

Apo(a) phenotypes and lp(a) concentrations in renal transplant patients.

Plasma lipoprotein (a) (LP(a)) concentrations are increased in patients with end-stage renal disease. Considering the influence of the apolipoprotein (a) (Apo(a)) polymorphism and the mode of dialysis in this prospective longitudinal study, we compared Lp(a) concentrations before and after the first 6 months of a successful kidney transplantation in 125 recipient patients. Apo(a) phenotyping was performed by using SDS-PAGE and SDS-agarose, isoforms were classified into high molecular weight (HMW) and low molecular weight (LMW). Before the graft, the Lp(a) concentrations were significantly higher in CAPD than in hemodialysis patients (p = 0.021). Six months after transplantation, Lp(a) fell in both treatment groups. This decrease occurred within both LMW and HMW but to a different extent: median relative variations were -35 and -50%, respectively (p = 0. 048). Among patients with Lp(a) concentration >30 mg/dl 6 months after transplantation, 74% had LMW Apo(a) isoform while the remaining 26% had HMW isoform. Successful renal transplantation leads rapidly to a correction of Lp(a) concentrations, especially in patients treated with CAPD who have higher Lp(a) levels. The most important factor seems to be the LMW status corresponding to high Lp(a) levels.