Decomposition of lipid hydroperoxides enhances the uptake of low density lipoprotein by macrophages.

This study examined the roles of low-density lipoprotein (LDL) lipid oxidation and peroxide breakdown in its conversion to a form rapidly taken up by mouse peritoneal macrophages. Oxidation of the LDL without decomposition of the hydroperoxide groups was performed by exposure to gamma radiation in air-saturated solutions. Virtually complete decomposition of the hydroperoxides was achieved by treatment of the irradiated LDL with Cu2+ under strictly anaerobic conditions. No uncontrolled LDL uptake by macrophages occurred when the lipoprotein contained less than 150 hydroperoxide groups per particle. More extensively oxidized LDL was taken up and degraded by mouse macrophages significantly faster than the native lipoprotein. The uptake was greatly enhanced by treatment of the oxidized LDL with Cu2+. A significant proportion of the LDL containing intact or copper-decomposed LDL hydroperoxide groups accumulated within the macrophages without further degradation. Treatment of the radiation-oxidized LDL with Cu2+ was accompanied by aggregation of the particles. Competition studies showed that the oxidized LDL was taken up by macrophages via both the LDL and the scavenger receptors, whereas the copper-treated lipoprotein entered the cells only by the scavenger pathway. Phagocytosis also played an important role in the metabolism of all forms of the extensively modified LDL. Our results suggest that minimally-oxidized LDL is not recognized by the macrophage scavenger receptors unless the lipid hydroperoxide groups are decomposed to products able to derivatize the apo B protein.

Increased oxidizability of plasma lipoproteins in diabetic patients can be decreased by probucol therapy and is not due to glycation.

Atherosclerosis is considered to be the major complication of diabetes mellitus. Since diabetic patients have increased blood levels of lipid peroxidation products we investigated whether the susceptibility of blood components to oxidation is altered in this disease. We analysed the parameters characterizing the extent of oxidative change and the antioxidant status of low density lipoprotein (LDL) and high density lipoprotein (HDL) in a group of diabetic patients and in a control population. LDL oxidizability was significantly higher for patients (P = 0.001) than for individuals in the control group. There were no significant differences in the alpha-tocopherol content or levels of performed peroxides in LDL samples isolated from diabetic patients and control individuals which could account for this effect. Similarly, LDL glycation, common in diabetes mellitus, was not responsible, since LDL glycated in vitro was more rather than less resistant to oxidation. Even the presence of unbound glucose at normal or elevated physiological concentrations had a delaying effect on the oxidation of LDL. The increased oxidizability of LDL isolated from diabetic patients could be reduced to control levels by a 6-week standard treatment with Probucol, originally applied to reduce their blood cholesterol.

Vitamin E content and low density lipoprotein oxidizability induced by free radicals.

Human LDL, HDL and lipoprotein deficient plasma isolated from 15 normal subjects was exposed to oxygen free radicals generated by gamma rays and the formation of peroxides and changes in levels of LDL alpha-tocopherol were measured. LDL exhibited an initial resistance against oxidation stress when compared to HDL. The results obtained for different individuals showed that there was no correlation between the initial levels of vitamin E in LDL or plasma and the amount of peroxide formed after exposure of the LDL to a standard quantity of oxygen radicals. Kinetic experiments with original LDL and LDL containing incorporated alpha-tocopherol demonstrated that the vitamin performed its antioxidant role by conferring some early protection to the lipids, being consumed in the process, but it was clear that additional factors are also instrumental in determining the total antioxidant potential of the human LDL.