Cell-mediated oxidation of low-density lipoprotein: the elusive mechanism(s)

Low-density lipoprotein (LDL) oxidation is believed to be causal in the process of atherosclerosis. Evidence suggests that this oxidation occurs in the arterial intima and is almost certainly mediated by the surrounding cells. Mechanisms by which cells could promote oxidation may be one or more of the following: 1. direct action of cell-derived oxidants (e.g. hydrogen peroxide, superoxide radical, hypochlorous acid, peroxynitrous acid); 2. transfer of cell-derived lipid hydroperoxides to LDL; 3. exposure of LDL to cell-derived oxidizing enzymes (e.g. lipoxygenase) which use LDL directly as a substrate; 4. maintenance of transition metals in a reduced and therefore highly reactive state (e.g. by thiols or other mechanisms); 5. generation of a local microenvironment (e.g. modulation of pH, pO2, antioxidants) which promotes metal-catalysed lipid peroxidation. In vitro cell-mediated LDL oxidation is absolutely metal-dependent and although the mechanism involved is not yet defined, evidence to date is most consistent with maintenance of metals in the reduced state as the predominant route.