Forum: role of oxidation in atherosclerosisThe oxidative modification hypothesis of atherogenesis: an overview
Introduction
The proposition that oxidative modification of low-density lipoprotein (LDL) enhances its atherogenicity is less than 20 years old. It was originally proposed by two groups coming from quite different directions. A group in Cleveland observed that LDL in cell culture could injure cells [1] and went on to show that the injury depended upon oxidative modification of LDL [2], [3], [4]. A group at the University of California, San Diego, recognizing that native LDL could not induce foam cell formation, demonstrated that cultured cells could modify LDL in the medium to a form recognized by scavenger receptors on the macrophage [5], [6] and went on to show that this was the result of oxidative modification [7]. The pace at which research in this area subsequently expanded is extraordinary. In 1989, there were only 25 papers in PubMed identifiable by the key phrase oxidized LDL; 10 years later, the number was 324 [8]. The reviews collected in this issue document how much our understanding of the role of oxidized LDL has expanded. Indeed, the literature is so extensive that we will make no attempt to present another comprehensive review here. Instead, we would like to put the current status of the field into perspective and to make comments about a few particular aspects of it.
We should first emphasize that the term oxidized LDL does not define a well-characterized molecular species. Far from it! Different laboratories use different conditions of oxidation, and the extent to which the LDL gets oxidized varies considerably. Even if the conditions for oxidative modification are rigidly defined and religiously adhered to, there will still be large variations depending upon the nature of the original LDL sample. Some may have much higher concentrations of endogenous antioxidants than others (vitamin E, ubiquinone, and others) and thus the extent of oxidation will vary from one preparation to the next. Originally, the term oxidized LDL was used to designate LDL preparations that had acquired new functions as a result of oxidation, such as an ability to cause damage to cultured cells or the ability to cause cholesterol accumulation in macrophages via scavenger receptors. For some purposes, such a functional definition is useful because these functional changes, although they tend to correlate to some extent with physical and chemical changes occurring during oxidation, do not closely parallel them in all instances. For example, more limited oxidations of LDL can be achieved that increase lipid peroxides but do not generate ligands for scavenger receptors (e.g., minimally modified LDL [9] or UV-irradiated LDL [10]).
Native LDL is itself heterogeneous, and one would hardly expect a homogenous product from the oxidation of an initially heterogeneous mixture. When one considers the complexity of the LDL particle and the huge numbers of oxidation-sensitive components in it, it becomes readily apparent that there could be an almost infinite range of products with varying degrees of oxidation of cholesterol, the phospholipids, the cholesteryl esters, the triglycerides, and the protein [11]. Consequently, care must be taken in interpreting the literature, especially if investigators have used different methods for oxidizing the LDL. The hope is that with further sophistication in analysis, we may be able ultimately to correlate the functional changes more precisely with physical and chemical changes in the oxidized LDL product. In some instances, we have to settle for an explicit and careful definition of how the oxidized LDL was prepared and for characterization by some of the available methods, however crude they may be. For most purposes, there are clear advantages to trying to refine the functional definitions of oxidized LDL to include the identification of the oxidized LDL moiety responsible for the functional changes.
Section snippets
Does oxidative modification of LDL play a quantitatively significant role in atherogenesis?
The current evidence supporting an oxidation theory for atherosclerosis falls into four main categories: (i) studies showing that oxidation of LDL accompanies the disease process and that oxidized lipoproteins are indeed present in vivo, particularly in arterial lesions; (ii) studies showing that a large number of the biological effects of oxidized LDL in vitro mimic events believed to be critical in the generation of atherosclerotic lesions in vivo; (iii) reports of antioxidants inhibiting or
Where and how is LDL oxidized in vivo?
A number of the papers in this Forum focus on potential redox signaling pathways pertinent to lesion development, including that by Patel et al. describing possible roles of both nitrogen and oxygen species [90]. There are lingering uncertainties about the mechanism of LDL oxidation in vivo. It is simply not yet known what the cellular sources of free radicals are, nor how LDL is oxidized in vivo. Early studies focused on LDL oxidation by endothelial and smooth muscle cells [4], [7], [91], but
Summary comments
What data would help in discriminating whether the oxidation hypothesis has merit? What are the high priorities? Certainly, determining how LDL gets oxidized in vivo will advance the process of finding ways to keep it from happening at a rate so high that macrophages and other physiological protectors cannot accommodate the products. Second, successful elucidation of which among the myriad putatively atherogenic effects oxidized LDL has on cultured cells contributes in vivo to lesion
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Guy Chisolm received a B.S. from the University of Pennsylvania and Ph.D. from the University of Virginia. Following postdoctoral fellowships at the Karolinska Institute and Massachusetts Institute of Technology, he joined the faculty of Case Western Reserve University in Cleveland. Since 1985, he has been in the Department of Cell Biology of the Cleveland Clinic Foundation. A few years after receiving an M.D. from Wayne State University and a Ph.D. with distinction from Harvard University, Dr. Daniel Steinberg began his research career at the NIH. In 1968, he became the head of the Division of Endocrinology and Metabolic Disease, School of Medicine, University of California, San Diego. Dr. Steinberg is a member of the National Academy of Sciences and the Institute of Medicine. Over the last two decades, studies in the laboratories of Drs. Chisolm and Steinberg have helped to shape the oxidative modification hypothesis of atherosclerosis.