Low density lipoprotein undergoes oxidative modification in vivo.

Abstract

It has been proposed that low density lipoprotein (LDL) must undergo oxidative modification before it can give rise to foam cells, the key component ofthe fatty streak lesion of atherosclerosis. Oxidation of LDL probably generates a broad spectrum of conjugates between fragments of oxidized fatty acids and apolipoprotein B. We now present three mutually supportive lines of evidence for oxidation of LDL in vivo: (i) Antibodies against oxidized LDL, malondialdehyde-lysine, or 4-hydroxynonenal-lysine recognize materials in the atherosclerotic lesions of LDL receptor-deficient rabbits; (ii) LDL gently extracted from lesions of these rabbits is recognized by an antiserum against malondialdehyde-conijugated LDL; (iii) autoantibodies against malondialdehyde-LDL (titers from 512 to >4096) can be demonstrated in rabbit and human sera.A growing body of evidence suggests that oxidative modification of low density lipoprotein (LDL) enhances its atherogenicity (for review see ref. 1). Monocyte-derived macrophages, the precursor of most foam cells in early atherosclerotic lesions, cannot take up native LDL rapidly enough to cause lipid loading (2). Oxidative modification converts LDL to a form recognized by the macrophage acetyl-LDL receptor (1, 2) and possibly by other receptors as well (3). This is true whether the oxidation is effected by incubation under appropriate conditions with cultured cells or by autooxidation catalyzed by Cu2+ ions in the absence of cells. Oxidative modification of LDL is accompanied by extensive degradation of its polyunsaturated fatty acids, generating a complex array of shorter chain-length fragments (4). During the oxidation, some of these fragments become covalently linked to apolipoprotein B (5), and much ofthis conjugation involves the E-amino groups of lysine residues. This chemically modified form of apolipoprotein is recognized by the acetyl-LDL receptor (6). Thus we can generate models for oxidized LDL by conjugating the apolipoprotein with single compounds generated during oxidation. Fogelman et al. (7) demonstrated that malondialdehyde (MDA)-conjugated LDL is so recognized. If oxidized LDL contains lysine residues conjugated with a variety of fatty acid fragments of different chain lengths, it should react with antibodies against a variety of such lysine derivatives. We previously showed that immunization of animals with autologous LDL modified by conjugation of lysine groups with glucose yields antisera directed specifically against glucitollysine (8) and that antibodies generated by injection of carbamoylated autologous LDL generates antisera that recognize the carbamoyllysine-not only in LDL but in other conjugated proteins as well (9). In other words, the specificity of these antisera is for very narrowly defined "X"-lysine adducts.The present studies, which use immunochemical methods, offer three lines of evidence that oxidation of LDL occurs in vivo.

Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study

“…Nonetheless in spite of our failure to demonstrate a signi®cant change in in vitro plasma antioxidant capacity following rutin supplementation, the possibility that the increased plasma concentration of¯avonoids may afford a protective effect by metal chelation still remains. In vivo the oxidation of LDL has been shown to be a mediating factor in atherosclerosis development (Aviram, 1983;Palinski et al, 1989;Steinberg et al 1989) and Fuhrman et al (1995) have reported a 20% reduction in the propensity of plasma to undergo oxidation following 2 weeks of supplementation with 400 ml red wineaday. Recently McAnlis et al, (1999) have shown that, although dietarȳ avonoids are extensively absorbed, they do not accumulate within the LDL but are tightly bound to plasma proteins located predominantly within the HDL fraction.…”

IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

“…Specifically, adaptive responses to OxLDL have been shown to increase during disease progression, but their exact role in atherogenesis is uncertain (18,19). Notably, in cholesterol-fed apoE -/-mice, advanced stages of atherosclerosis are associated with increased accumulation of OxLDL (20), and in this setting there is an immune deviation of OxLDL-specific Th1 responses toward Th2 (21,22).…”

LDL-cholesterol lowering and atherosclerosis - clinical benefit and possible mechanisms: an update

“…In addition to promoting excess lipid accumulation, oxidised LDL may facilitate the progression of atherosclerotic lesion by disrupting normal endothelial cell function [104]. The finding of oxidised LDL and lipid peroxides in areas of athero sclerotic plaques and the observation that antioxidant treatment with probucol and vitamin E slows the progression of atherosclerosis in the animal model strongly support the role of LDL modification in atherogenesis [105][106][107][108][109]. Recently the results of a randomized, controlled trial of vitamin E in normocholesterolaemic subjects with CAD, the Cambridge Heart Antioxidant Study (CHAOS), were published [110].…”

“…The initial inciting event in atherosclerosis is intimal lipid deposition, which is followed by re cruitment of inflammatory cells (monocytes and Tlymphocytes) into the intima, smooth muscle cell accumulation, and elaboration of collagen and matrix proteins by smooth muscle cells. These processes have been shown to be mediated by minimally modi fied LDL, and induces the expression of and inter play between adhesion molecules (selectins, ICAM-1, and VCAM-1), monocyte chemotactic proteins (e.g., MCP-1), growth factors (e.g., PDGF), and cytokines IL-l, IL-4, IL-6 , TNFot, and INF7 ) [103,133,134], It has been shown that systemic administration of oxidised LDL stimulates leucocyte adhesion and platelet aggregation to the vascular endothelium [135], In both man and rabbits, autoantibodies are found which recognize and selectively bind oxidised LDL [105]. Moreover, the titre of autoantibodies binding malondialdehyde-LDL was found to be an independent predictor of the progression of carotid atherosclerosis in man [136].…”