MDA-LDL

Iribarren, C. et al.. Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies against MDA-LDL with carotid atherosclerosis a case-control %Vady, Arterioscler. Thromb. Vase. Biol, 17, 1171, 1997. 

Both circulating OxLDL and MDA-LDL have been measured in plasma by ELISA. Most commonly, the capture antibody is a monoclonal antibody against OxLDL or MDA-LDL and the detection antibody, a polyclonal or monoclonal antibody directed against apo B (El, S12, Tl). Usually, the capture antibody is developed against chemically modified MDA-LDL or OxLDL but antibody has been developed against homogenate of human arteriosclerotic plaque. This antibody reacted with oxidized phosphatidylcholines but not native LDL, or MDA-LDL (S12). 

Holvoet et al. have used an ELISA to measure OxLDL and MDA-LDL with an assay based on inhibition of binding of mouse monoclonal antibodies to copper-modified LDL coated on a microtiter plate (H6). The samples... 

Three specific human monoclonal IgG autoantibodies that recognize oxidized MDA-LDL have been prepared using phage libraries (S6). Such a panel of antibodies may be of value in defining the composition of arteriosclerotic plaques in various stages of development (G2). They may also be directed at cells, lipoproteins, and matrix molecules in a way that can help identify the source of OxLDL in humans. Such human antibodies may also be used in assays. There is still a good deal of research needed to sort out these questions. 

In contrast to MDA and hydroxynonenai, other aldehyde products of lipid peroxidation are hydrophobic and remain closely associated with LDL to accumulate to mil-limolar concentrations. Aldehydes at these elevated levels react with the protein portion of the LDL molecule, apolipoprotein B (apoB). Accumulated aldehydes bind the free amino groups from lysine residues in addition to other functional groups (-OH, -SH) on the apoB polypeptide. Consequently, the protein takes on a net negative charge and complete structural rearrangement results in the formation of ox-LDL. ox-LDL is no longer recognized by the LDL receptor, and has several pro-inflammatory properties (discussed below). 

Rodenas et al. [77] studied PMN-stimulated lipid peroxidation of arachidonic acid. As MDA formation was inhibited both with L-arginine (supposedly due to the formation of excess NO) and DTPA (an iron ion chelator), it was concluded that about 40% of peroxidation was initiated by hydroxyl radicals formed via the Fenton reaction and about 60% was mediated by peroxynitrite. However, it should be noted that the probability of hydroxyl radical-initiated lipid peroxidation is very small (see above). Phagocyte-mediated LDL oxidation is considered below. 

Oxidized LDL are considered to be one of the major factors associated with the development of atherosclerosis. The earliest event is the transport of LDL into the arterial wall where LDL, being trapped in subendothelial space, are oxidized by oxygen radicals produced by endothelial and arterial smooth muscle cells. The oxidation of LDL in the arterial wall is affected by various factors including hemodynamic forces such as shear stress and stretch force. Thus, it has been shown [177] that stress force imposed on vascular smooth muscle cells incubated with native LDL increased the MDA formation by about 150% concomitantly with the enhancement of superoxide production. It was suggested that oxidation was initiated by NADPH oxidase-produced superoxide and depended on the presence of metal ions. 

Exposure of LDL to free radicals leads to lipid peroxidation and to a progressive loss of vitamin E and carotenoid within 6h. Thereafter the polyunsaturated fatty acids 18 2 and 20 4 are degraded in a lipid-peroxidation process [17] and a large variety of aldehydes is formed the following have been identified and quantified 4-hydroxyhexanal, 4-hydroxyoctenal, 4-hydroxynonenal, propanal, butanal, pentanal, hexanal, 2,4-heptadienal and malonaldehyde (MDA). 

Oxidative modification of LDL renders it immunogenic, and antibodies to the epitope of Ox-LDL, such as malondialdehyde (MDA)lysine, are found in serum and recognise material in atheromatous tissue [41,42]. However, until recently, there has been no prospective study to assess the importance of Ox-LDL among patients with vascular disease. 

A recent study [42] compared the titre of autoantibodies to malondialdehyde (MDA)-modified LDL and native LDL in baseline serum samples of 30 Eastern Finish men with accelerated two-year progression of carotid atherosclerosis and 30 age-matched controls without progression. Neither group had specific antibody binding to native LDL. A titre was defined as the ratio of antibody... 

The antiatherosclerotic effect of proanthocyanidin-rich grape seed extracts was examined in cholesterol-fed rabbits. The proanthocyanidin-rich extracts [0.1% and 1% in diets (w/w)] did not change the serum lipid profile, but reduced the level of the cholesteryl ester hydroperoxides (ChE-OOH) induced by 2,2/-azo-bis(2-amidinopropane-dihydrochloride (AAPH), the aortic malonaldehyde (MDA) content and severe atherosclerosis. The immuno-histochemical analysis revealed a decrease in the number of the oxidized LDL-positive macrophage-derived foam cells on the atherosclerotic lesions of the aorta in the rabbits fed the proanthocyanidin-rich extract. When the proanthocyanidin-rich extract was administered orally to the rats, proantho-cyanidin was detected in the plasma. In an in vitro experiment using human plasma, the addition of the proanthocyanidin-rich extract to the plasma inhibited the oxidation of cholesteryl linoleate in the LDL, but not in the LDL isolated after the plasma and the extract were incubated in advance. From these results, proanthocyanidins of the major polyphenols in red wine might trap ROSs in the plasma and interstitial fluid of the arterial wall, and consequently display antiatherosclerotic activity by inhibiting the oxidation of the LDL [92]. 

LDL, such as flbronectin, collagen, and laminin. MDA-modifled fibronectin is present in atherosclerotic plaques. Elevated levels of autoAbs directed against ApoB peptides, aldehyde-modified fibronectin and laminin reduce the risk of cardiovascular diseases." ... 

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