The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis.

C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta2-glycoprotein I (beta2GPI), implicating oxLDL/beta2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/beta2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of atherosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta2GPI complexes correlated with total cholesterol and hemoglobin A1c. Thus, the generation of CRP/oxLDL/beta2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/beta2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.

Clinical significance of serum oxidized low-density lipoprotein/beta2-glycoprotein I complexes in patients with chronic renal diseases.

BACKGROUND: Peroxidation of low-density lipoprotein (LDL) plays an important role in the development of dyslipidemias associated with the progression of chronic renal disorders. We recently reported [J Lipid Res 2001;42:697, 2002;43:1486, 2003;44:716] that oxidized LDL (oxLDL) interacts with an endogenous plasma protein, beta2-glycoprotein I (beta2GPI), via specific ligands. In the present study, the prevalence and clinical significance of oxLDL/beta2GPI complexes were evaluated in patients with chronic renal disorders. METHODS: Serum levels of oxLDL/beta(2)GPI complexes were measured by ELISA in patients with chronic renal disease and their association with clinical manifestations was assessed. RESULTS: The serum levels of oxLDL/beta2GPI complexes were significantly higher in patients with chronic renal failure (CRF), chronic nephritis (CN) and diabetes mellitus than those in healthy individuals. The presence of complexes in patients with CN was significantly associated with high dietary protein and sodium chloride intake, but not with lipid metabolic parameters. Malondialdehyde-modified LDL was significantly associated with total cholesterol and LDL cholesterol in all patient groups, but did not correlate with renal function parameters. CONCLUSIONS: Serum oxLDL/beta2GPI complexes, generated by oxidative stress and associated with high dietary protein and salt intake, might be a novel risk factor and a diagnostic marker for the development of chronic renal diseases, especially IgA nephropathy.

Significance of 8-hydroxy-2'-deoxyguanosine levels in patients with chronic renal failure.

The aim of this study was to determine the significance of 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is known as a marker of oxidative stress in vivo, in patients with chronic renal failure (CRF). Fifty-one non-dialysed CRF patients (29 men and 22 women; mean +/- SD age, 57.8 +/- 12.8 years) who were under dietary therapy for at least 6 months were enrolled in the study. Both serum and urinary 8-OHdG levels were measured by using high-sensitive enzyme-linked immunosorbent assay (ELISA) kits. We examined the relationship between 8-OHdG levels and clinical indices in patients with CRF. As a result, the serum 8-OHdG level was strongly correlated with serum levels of urea nitrogen (UN; r = 0.58; P < 0.0001), creatinine (Cr; r = 0.53; P < 0.0001), and beta2-microglobulin (beta2-MG; r = 0.54; P < 0.0001). Furthermore, the serum 8-OHdG level was inversely correlated with creatinine clearance (Ccr; r = -0.54; P < 0.0001). In contrast, urinary 8-OHdG level was not correlated with any of the clinical parameters. This is the first report of 8-OHdG level determination in patients with CRF. It is suggested that serum 8-OHdG level is not sufficient as a marker of oxidative damage in patients with CRF, and it should be corrected according to the residual renal function to estimate the accurate degree of oxidative stress.

Anti-beta 2-glycoprotein I autoantibodies and atherosclerosis.

beta 2-Glycoprotein I (beta 2-GPI) is a major antigen for antiphospholipid antibodies (aPL) present in patients with antiphospholipid syndrome (APS). We previously reported that beta 2-GPI specifically binds to oxidized low-density lipoprotein (oxLDL). Further, a ligand specific for beta 2-GPI, oxLig-1, purified from the extracted lipids of oxLDL was identified as 7-ketocholesterol-9-carboxynonanoate (i.e., 9-oxo-9-(7-ketocholest-5-en-3 beta-yloxy) nonanoic acid) OxLig-1 was recognized by beta 2-GPI and subsequently by anti-beta 2-GPI autoantibodies. Binding of liposomes containing oxLig-1 to macrophages were significantly enhanced in the presence of both beta 2-GPI and an anti-beta 2-GPI autoantibody derived from (NZW x BXSB) F1 mouse, an animal APS model, or from APS patients. Anti-beta 2-GPI autoantibodies derived from APS patients with episodes of arterial thrombosis were detected in ELISA, using a solid phase beta 2-GPI complex with oxLig-1. It was also reported that LDL-receptor-deficient mice that were fed a chow diet and immunized with beta 2-GPI had an accelerated atherosclerosis and that beta 2-GPI was abundantly expressed within subendothelial regions and intimal-medial borders of human atherosclerotic plaques. All of these observations strongly suggest that autoimmune atherogenesis linked to beta 2-GPI interaction with oxLDL and autoantibodies may be present in APS.