Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Iron chelators interfere with phagocyte-derived myeloperoxidase-mediated native low density lipoprotein oxidation

Lipid peroxidation is a major contributor in the pathogenesis of atherosclerosis. Oxidized low density lipoprotein (oxLDL) is recognized by scavenger receptors on monocyte derived macrophages which attach and migrate to the intima under various chemotactic gradients. The uncontrollable uptake of oxLDL results in the formation of foam cells, which will eventually contribute to atherogenic plaque formation. Among the various pathways whereby low-density lipoprotein is oxidized is by products from the reaction between neutrophil myeloperoxidase (MPO) and H2O2. Iron and copper have also been implicated in oxLDL formation.

The aim of this study was to investigate the involvement of iron and iron chelators in the in vitro oxidation of human, native LDL. The iron chelators deferoxamine, deferiprone and the experimental iron chelator CP502 were used. Their contribution in the MPO/H2O2 and Copper(II)-catalyzed oxidation of LDL was examined. The activity of the heme containing MPO enzyme was also monitored in the presence of these compounds. 10 µmol/L deferoxamine and 30 µmol/L of each deferiprone and CP502 inhibited the rate of diene formation in both catalyzed reactions.

An increase in lag times of oxidation indicate that all three chelators act as antioxidants in the process of LDL oxidation. The enzymatic activity of MPO remained unchanged. Iron chelation can significantly inhibit LDL oxidation without affecting MPO enzymatic activity.

Conclusion: LDL oxidation is a pathway whereby iron could participate in the pathogenesis of atherosclerosis.

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