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(Circulation Research. 2002;90:333.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Vitamin E Oxidation in Human Atherosclerotic Lesions

Andrew C. Terentis, Shane R. Thomas, Jeanne A. Burr, Daniel C. Liebler, Roland Stocker

From the Biochemistry Group (A.C.T., S.R.T., R.S.), The Heart Research Institute, Camperdown, New South Wales, Australia; Department of Pharmacology and Toxicology (J.A.B., D.C.L.), College of Pharmacy, University of Arizona, Tucson, Ariz.

Correspondence to Professor Roland Stocker, The Heart Research Institute, 145 Missenden Rd, Camperdown, NSW, 2050, Australia. E-mail r.stocker{at}hri.org.au

Oxidation of low-density lipoproteins (LDL) is a key process in atherogenesis, and vitamin E (-tocopherol, TOH) has received attention for its potential to attenuate the disease. Despite this, the type and extent of TOH oxidation and its relationship to lipid oxidation in the vessel wall where lesions develop remain unknown. Therefore, we measured oxidized lipids, TOH, and its oxidation products, -tocopherylquinone (TQ), 2,3- and 5,6-epoxy--tocopherylquinones by gas chromatography–mass spectrometry analysis in human lesions representing different stages of atherosclerosis. We also oxidized LDL in vitro to establish "footprints" of TOH oxidation product for different oxidants. The in vitro studies demonstrated that tocopherylquinone epoxides are the major products when LDL is exposed to the one-electron (ie, radical) oxidants, peroxyl radicals, and copper ions, whereas TQ preferentially accumulates with the two-electron (nonradical) oxidants, hypochlorite, and peroxynitrite. In human lesions, the relative extent of TOH oxidation was maximal early in the disease where it exceeded lipid oxidation. Independent of the disease stage, TQ was always the major oxidation product with all products together representing <20% of the total TOH present, and the oxidation product profile mirroring that formed during LDL oxidation by activated monocytes in the presence of nitrite. In contrast, oxidized lipid increased with increasing disease severity. These results suggest that two-electron oxidants are primarily responsible for TOH oxidation in the artery wall, and that the extent of TOH oxidation is limited yet substantial lipid oxidation takes place. This study may have important implications regarding antioxidant supplements aimed at preventing LDL oxidation and hence atherogenesis.

Key Words: tocopherol • LDL oxidation • atherogenesis • hypochlorous acid

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