Low Density Lipoprotein Oxidation and Its Pathobiological Significance

Abstract

The fact that low density lipoprotein (LDL) 1The abbreviations used are: LDL, low density lipoprotein; SRA, scavenger receptor A; MM-LDL, minimally oxidized LDL; MCSF, macrophage colony-stimulating factor; OxLDL, oxidized LDL; apoB, apolipoprotein B; MCP-1, monocyte chemoattractant protein-1. is extremely susceptible to oxidative damage has been known for some time (1Ray B.R. Davisson E.O. Crespi H.L. J. Phys. Chem. 1954; 58: 841-846Crossref Scopus (36) Google Scholar, 2Schuh J. Fairclough G.F. Haschemeyer R.H. Proc. Natl. Acad. Sci. U. S. A. 1978; 75: 3173-3177Crossref PubMed Scopus (256) Google Scholar), 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 (3Basu S.K. Brown M.S. Ho Y.K. Goldstein J.L. J. Biol. Chem. 1979; 254: 7141-7146Abstract Full Text PDF PubMed Google Scholar, 4Weinstein D.B. Carew T.E. Steinberg D. Biochim. Biophys. Acta. 1976; 424: 404-421Crossref PubMed Scopus (82) Google Scholar). 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 (3Basu S.K. Brown M.S. Ho Y.K. Goldstein J.L. J. Biol. Chem. 1979; 254: 7141-7146Abstract Full Text PDF PubMed Google Scholar). The uptake of this acetylated LDL was by way of a new receptor designated theacetyl LDL receptor (later cloned and renamed scavenger receptor A (SRA) (5Kodama T. Freeman M. Rohrer L. Zabrecky J. Matsudaira P. Krieger M. Nature. 1990; 343: 531-535Crossref PubMed Scopus (843) Google Scholar). SRA, unlike the LDL receptor, is notdown-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 (6Henriksen T. Mahoney E.M. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1981; 78: 6499-6503Crossref PubMed Scopus (817) Google Scholar, 7Henriksen T. Mahoney E.M. Steinberg D. Ann. N. Y. Acad. Sci. 1982; 401: 102-116Crossref PubMed Scopus (65) Google Scholar, 8Henriksen T. Mahoney E.M. Steinberg D. Arteriosclerosis. 1983; 3: 149-159Crossref PubMed Google Scholar). 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 (7Henriksen T. Mahoney E.M. Steinberg D. Ann. N. Y. Acad. Sci. 1982; 401: 102-116Crossref PubMed Scopus (65) Google Scholar, 8Henriksen T. Mahoney E.M. Steinberg D. Arteriosclerosis. 1983; 3: 149-159Crossref PubMed Google Scholar). This cell-mediated modification turned out to be, very simply, oxidative modification (9Steinbrecher U.P. Parthasarathy S. Leake D.S. Witztum J.L. Steinberg D. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 3883-3887Crossref PubMed Scopus (1416) Google Scholar, 10Morel D.W. DiCorleto P.E. Chisolm G.M. Arteriosclerosis. 1984; 4: 357-364Crossref PubMed Google Scholar). The addition of antioxidants to the culture medium completely blocked cell-induced 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. Between 1985 and 1989, 62 papers were published about “oxidized LDL”; between 1992 and January 1997, 727 papers were published about “oxidized LDL.” This intense interest springs larg