OXIDATION OF LOW-DENSITY-LIPOPROTEIN UPON SEQUENTIAL EXPOSURE TO COPPER IONS

Copper-induced LDL oxidation is characterized by an 'induction phase' (lag phase) during which the endogenous antioxidants are consumed, fol lowed by a 'propagation phase' in which the LDL-associated polyunsatur ated fatty acids are oxidized. Oxidation products may play an importan t role in the propagation of the oxidative process in the arterial int ima as they increase the permeability of the damaged endothelium to va rious plasma components, including LDL. We therefore found it of inter est to investigate the kinetics of LDL oxidation in vitro under condit ions where LDL is sequentially exposed to Cu2+-induced oxidation. The results of our studies demonstrate that when native LDL is exposed to copper oxidation in a medium containing oxidized LDL, oxidation of the added LDL may be almost instantaneous. Furthermore, even when native LDL is added to 'oxidizing LDL' towards the end of the lag phase or du ring the propagation phase it becomes oxidized after a very short lag. This oxidation process, occurring in spite of the possible protective effect of the antioxidants present in the newly added LDL, indicates that although antioxidants prolong the latency period by preventing th e formation of active free radicals, when such radicals are present in the system, oxidation propagates. These results lend strong support t o the generally accepted paradigm regarding the mechanism of propagati on of lipid oxidation. In view of the effect of oxidation products on the permeability of the endothelium, the observed shortening of the la g period may result in a vicious cycle, independent of the LDL-associa ted antioxidants, leading to continuing oxidation and foam cell format ion.