Abstract
Most models of lipoprotein oxidation by free radicals have excluded macromolecular plasma components from the system. This limits their biological significance because oxidation of lipoproteins appears to occur in the intima in the presence of a plasma ultrafiltrate. Hemin, a product of in vivo hemoglobin degradation, binds and oxidizes purified lipoproteins. However, it is not known whether this occurs in the presence of plasma components that may sequester hemin. We found that hemin in serum diluted to protein levels of the extracellular fluid (10–30%) binds to low and high density lipoproteins (LDL, HDL) with association constants in the nmol/L range. In the presence of H2O2, hemin oxidizes both lipoproteins in diluted serum with formation of conjugated dienes, thiobarbituric acid reacting substances, and F2-isoprostanes. This appeared to be caused by the high affinity of hemin with LDL and by the Fe3+ liberated that remains associated with the particles after hemin is degraded. Spectrophotometric and fluorescence experiments and electrophoresis of porphyrins complex with LDL indicated that the heme ring is buried in the lipoprotein surface-monolayer with the carboxylic groups in contact with positive regions of the protein and the solvent. Human macrophages associated and degraded 3- to 4-times more hemin-oxidized LDL in diluted serum than native LDL. It is possible then that at sites of LDL accumulation in the extracellular intima, hemin and H2O2 production could cause oxidation with potential atherogenic consequences for cellular lipoprotein processing. This may occur even when other macromolecules of the extracellular fluid are present.—Camejo, G., C. Halberg, A. Menschik-Lundin, E. Hurt-Camejo, B. Rosengren, H. Olsson, G. I. Hansson, G-B. Forsberg, and B. Ylhen. Hemin binding and oxidation of lipoproteins in serum: mechanisms and effect on the interaction of LDL with human macrophages. J. Lipid Res. 1998. 39: 755–766.
Highlights
Most models of lipoprotein oxidation by free radicals have excluded macromolecular plasma components from the system
A current hypothesis is that oxidation of apoB-100containing lipoproteins occurs through several pathways in the arterial intima after they are trapped by their specific association with extracellular proteoglycans [5,6,7,8]
Conjugated dienes or thiobarbituric acid reacting substances (TBARS) was detectable over the values measured for the low density lipoproteins (LDL) samples containing no porphyrins, conjugated dienes Ͻ0.2 mol/mg apoB protein, and TBARS Ͻ2 nmol/mg apoB protein
Summary
Most models of lipoprotein oxidation by free radicals have excluded macromolecular plasma components from the system. With the use of surface- and core-located oxidizing fluorescent probes, it was shown that hemin changes the charge of purified LDL and oxidizes its core lipids more efficiently than free Fe3ϩ ions. This caused an increase in the LDL uptake by macrophages [15, 16]. Most studies concerning in vitro oxidation of lipoproteins with transition metals, free radical generating systems, and cells in culture have been carried out in the absence of plasma macromolecular components or at very low concentrations These conditions may limit the relevance of such models to the in vivo situation
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