Forum: role of oxidation in atherosclerosis
The oxidative modification hypothesis of atherogenesis: an overview

https://doi.org/10.1016/S0891-5849(00)00344-0Get rights and content

Abstract

The literature relating lipid and lipoprotein oxidation to atherosclerosis has expanded enormously in recent years. Papers on the “oxidative modification hypothesis” of atherogenesis have ranged from the most basic studies of the chemistry and enzymology of LDL oxidation, through studies of the biological effects of oxidized LDL on cultured cells, and on to in vivo studies of the effects of antioxidants on atherosclerosis in animals and humans. The data in support of this theory are mounting but many key questions remain unanswered. For example, while it is generally agreed that LDL undergoes oxidation and that oxidized LDL is present in arterial lesions, it is still not known how and where LDL gets oxidized in vivo nor which of its many biological effects demonstrable in vitro are relevant to atherogenesis in vivo. This brief review is not intended to be comprehensive but rather to offer a perspective and a context for this Forum. We discuss the strengths and weaknesses of each line of evidence, try to identify areas in which further research is needed, assess the relevance of the hypothesis to the human disease, and point to some of the potential targets for therapy.

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

References (133)

  • A.D. Watson et al.

    Structural identification of a novel pro-inflammatory epoxyisoprostane phospholipid in mildly oxidized low density lipoprotein

    J. Biol. Chem.

    (1999)
  • H.N. Hodis et al.

    Biochemical and cytotoxic characteristics of an in vivo circulating oxidized low density lipoprotein (LDL−)

    J. Lipid Res.

    (1994)
  • A. Sevanian et al.

    LDL− is a lipid hydroperoxide-enriched circulating lipoprotein

    J. Lipid Res.

    (1997)
  • S. Hörkkö et al.

    Immunological responses to oxidized LDL

    Free Radic. Biol. Med.

    (2000)
  • M. Navab et al.

    Pathogenesis of atherosclerosis

    Am. J. Cardiol.

    (1995)
  • D. Steinberg

    Low density lipoprotein oxidation and its pathobiological significance

    J. Biol. Chem.

    (1997)
  • G.M. Chisolm et al.

    Regulation of cell growth by oxidized LDL

    Free Radic. Biol. Med.

    (2000)
  • A. Carr et al.

    The role of natural antioxidants in preserving the biological activity of endothelium-derived nitric oxide

    Free Radic. Biol. Med.

    (2000)
  • P.L. Fox et al.

    Lipoprotein-mediated inhibition of endothelial cell production of platelet-derived growth factor-like protein depends on free radical lipid peroxidation

    J. Biol. Chem.

    (1987)
  • G. Jurgens et al.

    Modification of human serum low density lipoprotein by oxidation—characterization and pathophysiological implications

    Chem. Phys. Lipids

    (1987)
  • A. Sevanian et al.

    Characterization of endothelial cell injury by cholesterol oxidation products found in oxidized LDL

    J. Lipid Res.

    (1995)
  • S.M. Colles et al.

    Roles of multiple oxidized LDL lipids in cellular injurydominance of 7 beta-hydroperoxycholesterol

    J. Lipid Res.

    (1996)
  • J.P. Thomas et al.

    Lethal damage to endothelial cells by oxidized low density lipoproteinrole of selenoperoxidases in cytoprotection against lipid hydroperoxide- and iron-mediated reactions

    J. Lipid Res.

    (1993)
  • A.J. Brown et al.

    7-Hydroperoxycholesterol and its products in oxidized low density lipoprotein and human atherosclerotic plaque

    J. Lipid Res.

    (1997)
  • D.W. Morel et al.

    Antioxidant treatment of diabetic rats inhibits lipoprotein oxidation and cytotoxicity

    J. Lipid Res.

    (1989)
  • J.W. Heinecke

    Oxidants and antioxidants in the pathogenesis of atherosclerosisimplications for the oxidized low density lipoprotein hypothesis

    Atherosclerosis

    (1998)
  • D.A. Bird et al.

    Effect of probucol on LDL oxidation and atherosclerosis in LDL receptor–deficient mice

    J. Lipid Res.

    (1998)
  • M.P. de Winther et al.

    Scavenger receptor deficiency leads to more complex atherosclerotic lesions in APOE3Leiden transgenic mice

    Atherosclerosis

    (1999)
  • M.K. Cathcart et al.

    Lipoxygenases and atherosclerosisprotections versus pathogenesis

    Free Radic. Biol. Med.

    (2000)
  • S.J. Feinmark et al.

    Is there a role for 15-lipoxygenase in atherogenesis?

    Biochem. Pharmacol.

    (1997)
  • G.M. Chisolm et al.

    The oxidation of lipoproteins by monocytes-macrophages. Biochemical and biological mechanisms

    J. Biol. Chem.

    (1999)
  • P.L. Fox et al.

    Ceruloplasmin and cardiovascular disease

    Free Radic. Biol. Med.

    (2000)
  • K. Houglum et al.

    Excess iron induces hepatic oxidative stress and transforming growth factor beta1 in genetic hemochromatosis

    Hepatology

    (1997)
  • J.R. Hessler et al.

    Lipoprotein oxidation and lipoprotein-induced cytotoxicity

    Arteriosclerosis

    (1983)
  • D.W. Morel et al.

    Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation

    Arteriosclerosis

    (1984)
  • T. Henriksen et al.

    Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cellsrecognition by receptors for acetylated low density lipoproteins

    Proc. Natl. Acad. Sci. USA

    (1981)
  • T. Henriksen et al.

    Enhanced macrophage degradation of biologically modified low density lipoprotein

    Arteriosclerosis

    (1983)
  • U.P. Steinbrecher et al.

    Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids

    Proc. Natl. Acad. Sci. USA

    (1984)
  • J. Berliner et al.

    Oxidized lipids in atherogenesisformation, destruction and action

    Thromb. Haemost.

    (1997)
  • D. Steinberg

    Oxidized low density lipoprotein—an extreme example of lipoprotein heterogeneity

    Isr. J. Med. Sci.

    (1996)
  • Podrez, E. A.; Abu-Soud, H. M.; Hazen, S. L. Myeloperoxidase-generated oxidants and atherosclerosis. Free Radic. Biol....
  • S. Yla-Herttuala et al.

    Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man

    J. Clin. Invest.

    (1989)
  • W. Palinski et al.

    Low density lipoprotein undergoes oxidative modification in vivo

    Proc. Natl. Acad. Sci. USA

    (1989)
  • M.E. Haberland et al.

    Malondialdehyde-altered protein occurs in atheroma of Watanabe heritable hyperlipidemic rabbits

    Science

    (1988)
  • K.D. O’Brien et al.

    Oxidation-specific epitopes in human coronary atherosclerosis are not limited to oxidized low-density lipoprotein

    Circulation

    (1996)
  • W. Palinski et al.

    ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesisdemonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum

    Arterioscler. Thromb.

    (1994)
  • G. Jurgens et al.

    Immunostaining of human autopsy aortas with antibodies to modified apolipoprotein B and apoprotein(a)

    Arterioscler. Thromb.

    (1993)
  • M.E. Rosenfeld et al.

    Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts

    J. Clin. Invest.

    (1991)
  • M.K. Chang et al.

    Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophagesevidence that oxidation-specific epitopes mediate macrophage recognition

    Proc. Natl. Acad. Sci USA

    (1999)
  • Y.J. Geng et al.

    Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme

    Am. J. Pathol.

    (1995)
  • Cited by (693)

    • Role of oxidative stress in the pathogenesis of metabolic syndrome

      2023, Metabolic Syndrome: From Mechanisms to Interventions
    View all citing articles on Scopus
    1

    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.

    View full text