NATIVE LDL THAT IS OFTEN USED IN IN VITRO STUDIES MAY NOT REPRESENT NATIVE LDL IN PLASMA

Oxidized low density lipoprotein (Ox-LDL) has a plethora of components that are not present in native LDL. Their presence and quantity depends on the nature, type, and extent of oxidation. Lipids esterified to oxidized fatty acids are the major components formed during the early phase of oxidation and these show a number of proatherogenic properties in in vitro cell culture systems. Recently, evidence has been forthcoming to suggest that some of these oxidized lipids also could elicit “antioxidant–antiatherogenic” responses from cells. Moreover, some of the cellular effects of Ox-LDL that were previously interpreted as atherogenic could also be reinterpreted to suggest an antiatherogenic cellular response. In addition to the above, the antioxidants that are carried in lipoproteins could have anomalous behavior attributable to their metabolism, ability to be internalized by arterial cells, and the presence of oxidative systems that could render them prooxidants. In conclusion, there are numerous contributing factors that need to be studied and understood before antioxidant therapy becomes an option for the treatment for cardiovascular diseases. —Parthasarathy, S. , N. Santanam, S. Ramachandran, and O. Meilhac. Oxidants and antioxidants in atherogenesis: an appraisal. J. Lipid Res. 1999. 40: 2143–2157. Supplementary key words LDL • antioxidants • prooxidants • lipid peroxides • atherosclerosis It is now generally accepted that oxidation of low density lipoprotein (LDL) plays a significant pathogenic role in atherosclerosis (1, 2). More than 1,000 papers dealing directly or indirectly with the oxidation of LDL were published between January 1991 and the end of 1998. More details, supporting circumstantial evidence, and interpretations have been added to the hypothesis, and yet the hypothesis is currently at an impasse. Little, if any, has changed during the past few years regarding the answer to the question: do antioxidants prevent the progression of atherosclerotic lesions in humans? Despite a recent article sponsored by the American Heart Association concurring that there is no conclusive evidence to suggest that a daily supplement of antioxidant nutrients can prevent atherosclerosis (3), claims of beneficial actions of antioxidants have left both the public and the medical professionals confused. On the other hand, the success of basic research makes one wonder whether one needs to wait for the “right antioxidant,” e.g., a lipoxygenase inhibitor, trial in humans to advance the hypothesis. For example, several years ago there were studies that proposed that 12,15lipoxygenase initiates the oxidative process (4–6). Recently, Cyrus et al. (7) showed that apoE 2 / 2 /L-12O 2 / 2 doubleknockout mice (apoE and 12,15-lipoxygenase) developed less severe lesions than either the heterozygote mice or the parent apoE-deficient mice. In this review we will briefly discuss the current status of the basic research and rephrase the question: how far are we beyond cholesterol to suggest that oxidized components of LDL add to the atherogenicity of the particle? We will direct our questions to the presence of the key components, i.e., oxidized lipids, that make oxidized-LDL (Ox-LDL) more atherogenic. Ox-LDL has been suggested to have a plethora of proatherogenic effects (1, 2) that can be predominantly attributed to its lipid components. Ox-LDL was originally conceptualized to account for the enhanced uptake by macrophages by way of scavenger receptor (8, 9). Products generated from the decomposition of peroxidized lipids, such as aldehydes, were supposed to modify apolipoprotein B-100 (apoB-100) to a more electronegative form capable of interacting with the macrophage scavenger receptor (s) (10, 11). This feature of the protein appeared to be one of the few distinguishing characteristics of Ox-LDL that was touted as an obligatory feature for its interaction with cell surface receptors. Based on this, a number of cell surface proteins were identified as putative receptors for Ox-LDL (8, 12–16). Recently, based on the ability of the lipids of the Ox-LDL to compete for the uptake and degradation of Ox-LDL by macrophages, the presence of potential ligands for the scavenger receptors in the lipid phase was suggested (17). However, these studies do not exclude proteolipids (lipophilic proteinlipid components) that could be present in the lipid phase as potential competitors. Abbreviations: LDL, low density lipoprotein; Ox-LDL, oxidized LDL; EDTA, ethylenediaminetetraacetic acid; PUFA, polyunsaturated fatty acids; CHD, coronary heart disease, lysoPtdCho, lysophosphatidylcholine. 1 To whom correspondence should be addressed. review by gest, on S etem er 0, 2017 w w w . j.org D ow nladed fom