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The oxidative modification hypothesis of atherogenesis: an overview.

N2 - 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. (C) 2000 Elsevier Science Inc.

AB - 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. (C) 2000 Elsevier Science Inc.

The oxidative modification hypothesis of atherogenesis…

hypothesis of atherogenesis: an overview.

modification hypothesis of atherogenesis: an overview

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. (C) 2000 Elsevier Science Inc.

The accumulated evidence that oxidative modification of LDL plays an important role in the pathogenesis of atherosclerosis in animal models is very strong. The negative results in recent clinical studies have caused many to conclude that LDL oxidation may not be relevant in the human disease. Yet many of the lines of evidence that support the hypothesis have been demonstrated to apply also in humans. In this review, we briefly summarize the lines of evidence on which the hypothesis rests, its strengths, and its weaknesses.

The LDL modification hypothesis of atherogenesis: an …

In 1981, Henriksen et al. () discovered that native LDL simply incubated overnight with cultured endothelial cells was converted to a form (endothelial cell-modified LDL) that was recognized specifically and with high affinity by peritoneal macrophages. They proposed that this endothelium-induced modification of LDL might be the missing step that permits rapid LDL uptake and foam cell formation. Later studies showed that during its incubation with endothelial cells (and with a number of other cell types), LDL was undergoing an oxidative modification (, ). This was the genesis of the so-called oxidative modification hypothesis of atherogenesis. Certainly the hypothesis has been heuristic; PubMed lists over 5,000 papers published to date under “oxidized LDL” and over 2,200 indexed under “oxidized LDL and atherosclerosis,” Over 1,000 in the latter category have been published in the past 5 years alone. So the hypothesis is very much alive. Studies in animal models of atherosclerosis continue to strongly support the hypothesis. However, a series of negative clinical trials using vitamin E or β-carotene have raised doubts about the relevance of the hypothesis to the human disease. In this review, we attempt to assess the strengths and weaknesses of the evidence for the hypothesis and suggest future directions for research.

(2000) The oxidative modification hypothesis of atherogenesis: An overview.

Most of the large clinical trials of antioxidants have been done using vitamin E or β-carotene. Meta-analysis of the data from these large studies (n = ca. 80,000) shows no benefit at all with regard to cardiovascular outcomes (). There is no doubt that at the doses used (50–400 mg/d), vitamin E offered no protection against coronary heart disease in a general population. Do these disappointingly negative results mean that the oxidative modification hypothesis is irrelevant in the human disease? Not necessarily. As discussed elsewhere (), vitamin E may be the wrong antioxidant in humans, the dosage may have been too low, treatment may have been started too late in life, or antioxidant treatment may be beneficial only in some subset of patients subject to unusual oxidative stress (see below). After all, the hypothesis is not that any antioxidant, at any dosage, in any individual will necessarily be effective. The hypothesis is that oxidative modification plays a quantitatively significant role in pathogenesis. Of course, the implication is that one day an effective antioxidant intervention will be found that will slow the progress of the disease. It would be a mistake to ignore the strong scientific base of the hypothesis and assume prematurely that the human disease is categorically different from that in experimental animals, including the nonhuman primate ().

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The oxidative modification hypothesis of atherogenesis: an overview


The oxidative modification hypothesis of atherogenesis ..

These manifold effects of OxLDL have been mostly described in cell culture settings and in only a few instances have they been confirmed in the whole animal. The findings are compatible with and lend some support to the oxidative modification hypothesis, but until they are evaluated in intact animals they remain only suggestive. In vivo veritas.

The oxidative modification hypothesis of atherogenesis (An overview)

Effective antioxidants include probucol, probucol analogs, butylated-hydroxytoluene, N,N'-diphenylphenylenediamine, BO-653 (an analog of probucol), and vitamin E. The fact that these several compounds, quite different in structure and metabolism but sharing an ability to trap free radicals, have all been shown to act as inhibitors of atherosclerosis considerably strengthens the oxidative modification hypothesis. Further support comes from a study in which the protective effect of vitamin E was confirmed in apolipoprotein (apo) E-deficient mice and then shown to be almost abolished when the mice were also deficient in 12/15-lipoxygenase (). The authors suggest therefore that the protection afforded by vitamin E and that afforded by targeting 12/15-lipoxygenase share a final common pathway.

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