Role of oxidatively modified low density lipoproteins and anti-oxidants in atherothrombosis.
Retrospective studies have demonstrated an association between coronary artery disease (CAD) and increased plasma levels of oxidised low density lipoproteins (LDL). A very recent prospective study in heart transplant patients has demonstrated that oxidised LDL is an independent risk factor for transplant CAD, thus further supporting the hypothesis that oxidised LDL is actively involved in the development of CAD. The increase of circulating oxidised LDL is most probably caused by back-diffusion from the atherosclerotic arterial wall in the blood, independent of plaque rupture. Indeed, plasma levels of oxidised LDL were very similar in patients with stable CAD and in patients with acute coronary syndromes. These were, however, associated with increased release of malondialdehyde (MDA)-modified LDL. Oxidised LDL may be generated by radical-mediated or by lipoxygenase or phospholipase catalysed lipid oxidation, and by myeloperoxidase catalysed protein and lipid oxidation. Prostaglandin synthesis by endothelial cells under oxidative stress and platelet activation are associated with the release of aldehydes; these induce the oxidative modification of the apolipoprotein B-100 moiety of LDL in the absence of lipid peroxidation, and thus generate MDA-modified LDL. Efficient prevention of in vivo oxidation may involve efficient cholesterol lowering, improving the anti-oxidative status of LDL by increasing the anti-oxidant content and increasing the oleate content of LDL, and by shifting the LDL away from phenotype B (characterised by small dense LDL particles). Anti-oxidative and anti-inflammatory enzymes associated with HDL may inhibit the oxidation of LDL or reverse the atherothrombotic effects of LDL.
Holvoet
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Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. paul.holvoet@med.kuleuven.ac.be