Low Density Lipoprotein Oxidation and Its Pathobiological Significance

Abstract

BackgroundThe fact that low density lipoprotein (LDL) 1 is extremely susceptible to oxidative damage has been known for some time (1, 2), but until quite recently this was primarily a nuisance for the student of lipoprotein metabolism. It now appears that oxidation of LDL plays a significant role in atherogenesis.Beginning in the 1980s evidence began to accumulate that cholesterol accumulation in the developing atherosclerotic lesion was probably not due to the uptake of native LDL by way of the Brown/Goldstein LDL receptor but instead due to the uptake of some modified form of LDL (then still unidentified) by way of one or more alternative receptors (also then unidentified). This conclusion grew from two well accepted observations. First, patients and animals totally lacking the LDL receptor nevertheless accumulate cholesterol in foam cells much the same way as do patients and animals with normal LDL receptors; second, the two cell types in lesions that give rise to cholesterol-laden foam cells (the monocyte/ macrophage and the smooth muscle cell) do not accumulate cholesterol in vitro even in the presence of very high concentrations of native LDL (3, 4). This paradox could be resolved if circulating LDL underwent some form of modification and if the modified form, rather than native LDL itself, then served as the ligand for delivery of cholesterol to developing foam cells. Acetylation of LDL in vitro generated a modified LDL that could induce cholesterol accumulation in macrophages (3). The uptake of this acetylated LDL was by way of a new receptor designated the acetyl LDL receptor (later cloned and renamed scavenger receptor A (SRA) (5). SRA, unlike the LDL receptor, is not down-regulated when the cholesterol content of the cell increases. Thus, acetyl LDL could, in principle, account for foam cell formation. However, there was (and still is) no evidence that acetylation of LDL occurs to any extent in vivo. Another modified form of LDL emerged as a candidate when it was shown that simply incubating LDL overnight with a monolayer of arterial endothelial cells converted it to a form that was taken up much more rapidly by macrophages and capable of increasing their cellular cholesterol content (6 -8). The uptake was specific and saturable, and it occurred in part by way of the acetyl LDL receptor. Incubation with smooth muscle cells could also modify LDL in much the same way (7,8). This cell-mediated modification turned out to be, very simply, oxidative modification (9, 10). The addition of antioxidants to the culture medium completely blocked cellinduced modification, and the changes induced by the cells could be duplicated by incubating LDL in the presence of transition metals in the absence of cells. Thus, oxidative modification induced by cells appeared to be a biologically plausible modification of LDL that could account for foam cell formation and the initiation, or at least acceleration, of the atherosclerotic process.

The effect of whisky and wine consumption on total phenol content and antioxidant capacity of plasma from healthy volunteers

“…Such results do not necessarily indicate that phenolics are transported to cellular sites within peripheral tissues where they could exert important antioxidant function. However, epidemiological studies implying that consumption of antioxidant-rich foods reduces the risk of heart disease (Duthie & Brown, 1994) may indicate that certain phenolics or their metabolites can prevent in vivo oxidation of low density lipoproteins in the arterial intima, thus inhibiting formation of the atheromatous plaque (Furhman et al, 1995;Steinberg, 1997).…”

Two-photon microscopy of aorta fibers shows proteolysis induced by LDL hydroperoxides

“…Two features characterize the most common degenerative process of arterial wall, the focal formation of plaque with the related thrombotic outcome, and a diffuse loss of elastic properties due to thickening of the wall and to degradation of matrix fibers, also known as the vasculopathy of aging [1][2][3]. Degradation of matrix proteins, particularly elastin, is also involved in plaque rupture and aneurysm [4,16].…”

“…Age-dependent degeneration of the arterial wall involves increased wall thickness, decreased elasticity, disorganization and fragmentation of elastic fibers, and usually develops together with the formation of lipid plaque, the typical hallmark of atherogenesis [1][2][3]. Aneurysm formation and evolution involves degradation of matrix proteins [4].…”

Oxidized LDL immune complexes and oxidized LDL differentially affect the expression of genes involved with inflammation and survival in human U937 monocytic cells

“…Therefore, understanding the processes by which foam cells are formed has been a major objective of atherosclerosis research. It is well established that oxidized LDL (oxLDL) particles are taken up by macrophages leading to accumulation of cholesteryl esters (CE) (1,2). On the other hand, oxLDL is immunogenic and elicits the production of antibodies, predominantly of the proinflammatory IgG1 and IgG3 isotypes (3,4).…”