Oxidatively modified low-density lipoprotein

Quinn, M.T., Parthasarathy, S., Fong, L.G. and Steinberg, D. (1987). Oxidatively modified low-density lipoproteins a potential role in recruitment and retention of monocyte/ macrophages during atherogenesis. Proc. Nad Acad. Sci. USA 84, 2995-2998. 

Yla-Herttuala, S., Witztum, J.L. and Steinberg, D. (1989). Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions rabbit and man. J. Clin. Invest. 84, 1086-1095. 

Naito, M., Yamada, K., Hayashi, T., Asai, K., Yoshimine, N., Iguchi, A., 1994, Comparative toxicity of oxidatively modified low-density lipoprotein and lysophosphatidylcholine in cultured vascular endothelial cells, Heart Vessels 9 183-187. 

Oxidative stress is now widely believed to be the major mechanism of athero-genesis. Interestingly, it was demonstrated 47 years ago that atheromatous plaques contain abundant lipoperoxides and other lipid peroxidation products (G9). More recently, our understanding of this process was advanced when evidence was provided for significant free radical activity and the lipid oxidative modification hypothesis was presented (P10). A subsequent study provided further evidence that oxidatively modified low-density lipoproteins (LDL) play a major role in the formation of the fatty streak, the earliest visible atherosclerotic lesion, and the subsequent production of the atheroscelrotic plaque (S27). The proposed sequence, which involves arterial endothelial and smooth muscle cells, as well as mono-cytes/macrophages, is as follows (Ql, S25). 

Itabe H, Yamamoto H, Imanaka T, et al. (1996) Sensitive detection of oxidatively modified low density lipoprotein using a monoclonal antibody. J Lipid Res 37 45-53... 

In addition, an epidemiological study of 1931 selected men in Finland has indicated that increases in stored iron levels, as assessed by serum ferritin concentration, is a risk factor for coronary heart disease [60]. Iron mobilized from ferritin generates reactive oxygen radicals that presumably oxidatively modify low-density lipoproteins, thereby enhancing the risk of ischemic heart disease. 

Cell-membrane proteins that endocytose oxidatively or otherwise modified low-density lipoproteins. 

Parthasarathy, S., Putz, D.J., Boyd, D., Joy, L. and Steinberg, D. (1986). Macrophage oxidation of low density lipoprotein generates a modified form recognised by the scavenger receptor. Arteriosclerosis 6, 505-510. 

S. Parthasarathy, D. J. Printz, D. Boyd, L. Joy and D. Steinberg, D, Macrophage Oxidation of Low Density Lipoprotein Generates a Modified Form Recognized by the Scavenger Receptor, Arteriosclerosis 6 (1986) 505-510. 

Cvetkovic, J.T. et al. Increased levels of autoantibodies against copper-oxidized low density lipoprotein, malondialdehyde-modified low density lipoprotein and cardiolipin in patients with rheumatoid arthritis. Rheumatology (Oxford) 41 (2002) 988-95. 

Loidl, A. et al. Oxidized phospholipids in minimally modified low density lipoprotein induce apoptotic signaling via activation of acid sphingomyelinase in arterial smooth muscle cells. J Biol Chem. 278 (2003) 32921-8. 

Enhanced production of vasoconstrictor factors via eicosanoid and/or free radical-related mechanisms has been observed in several cardiovascular disease states. In addition to the well-established role of free radicals in promoting the oxidation of low density lipoprotein cholesterol (LDL-C), changes in free radical status may modify endogenous eicosanoid profiles and/or produce nonenzymatic lipid peroxidation products of the arachidonic acid (AA) cascade such as lipid hydroperoxides and isoprostanes, which have been shown to possess potent vasoactive properties (3). Furthermore, an excess of free radicals may interact with the vascular endothelial cell nitric oxide (NO) to produce highly reactive peroxynitrite radicals, resulting in tissue damage and vasoconstriction (4—6) (Fig. 2). 

Oxidized phospholipids (OxPLs) have been identified as an active eomponent in minimally modified low-density lipoproteins (LDLs), which is a proinflammatory form of LDL generated by mild oxidation of lipoproteins in the presence of... 

Yamaguchi Y, Matsuno S., Kagota S., Haginaka J., Kunitomo M. Oxidants in cigarette smoke extract modify low-density lipoprotein in the plasma and facilitate ath-erogenesis in the aorta of Watanabe heritable hyperlipidemic rabbits. 2001 156 109il7. 

Barenghi, L., Bradamante, S., Giudici, G.A. and Veigani, C. (1990). NMR analysis of low-density-lipoprotein oxidatively-modified in vitro. Free Rad. Res. Commun. 8, 175-183. 

Although atherosclerosis and rheumatoid arthritis (RA) are distinct disease states, both disorders are chronic inflammatory conditions and may have common mechanisms of disease perpetuation. At sites of inflammation, such as the arterial intima undergoing atherogen-esis or the rheumatoid joint, oxygen radicals, in the presence of transition-metal ions, may initiate the peroxidation of low-density lipoprotein (LDL) to produce oxidatively modified LDL (ox-LDL). Ox-LDL has several pro-inflammatory properties and may contribute to the formation of arterial lesions (Steinberg et /., 1989). Increased levels of lipid peroxidation products have been detected in inflammatory synovial fluid (Rowley et /., 1984 Winyard et al., 1987a Merry et al., 1991 Selley et al., 1992 detailed below), but the potential pro-inflammatory role of ox-LDL in the rheumatoid joint has not been considered. We hypothesize that the oxidation of LDL within the inflamed rheumatoid joint plays a pro-inflammatory role just as ox-LDL has the identical capacity within the arterial intima in atherosclerosis. 

Biotin-hydrazide has been used to biotinylate antibodies at their oxidized carbohydrate residues (O Shanessy et al., 1984, 1987 O Shanessy and Quarles, 1985 Hoffman and O Shannessy, 1988), to modify the low-density lipoprotein (LDL) receptor (Wade et al., 1985), to biotinylate nerve growth factor (NGF) (Rosenberg et al., 1986), and to modify cytosine groups in oligonucleotides to produce probes suitable for hybridization assays (Reisfeld et al., 1987) (Chapter 27, Section 2.3). 

Zieseniss, S. et al. Modified phosphatidylethanolamine as the active component of oxidized low density lipoprotein promoting platelet prothrombinase activity. J. Biol. Chem. 216... 

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