EFFECT OF HOMOCYSTEINE ON COPPER ION-CATALYZED, AZO COMPOUND-INITIATED, AND MONONUCLEAR CELL-MEDIATED OXIDATIVE MODIFICATION OF LOW-DENSITY-LIPOPROTEIN

Homocysteine is an independent risk factor for cardiovascular diseases . The mechanisms by which elevated plasma concentrations of homocystei ne are related to the pathogenesis of atherosclerosis are not fully un derstood. To examine whether homocysteine is implicated in atherogenes is through the modification of low density lipoprotein (LDL), the effe ct of homocysteine on the oxidation of LDL was studied by three differ ent oxidation systems. Thus, LDL was subjected to Cu2+-catalyzed, azo compound-initiated, and peripheral blood mononuclear cell-mediated oxi dative modification. The extent of modification was assessed by measur ing the formation of conjugated dienes, lipid peroxides, thiobarbituri c acid-reactive substances, and the relative electrophoretic mobility. Homocysteine at a normal plasma concentration (6 mu M) showed no effe ct, whereas a concentration corresponding to moderate hyperhomocystein emia (25 mu M) or to concentrations seen in homocystinuria patients (1 00, 250, and 500 mu M) protected LDL from modification of the lipid as well as of the protein moiety. One exception was observed: when the o xidation was initiated by copper ions, homocysteine at concentrations 6 and 25 mu M stimulated the lipid peroxidation of LDL to a small, but statistically significant cant extent. High concentrations of homocys teine showed antioxidative properties as long as the thiol groups were intact, thereby delaying the onset of the oxidation. The 1,1-diphenyl -2-picrylhydracyl radical test demonstrated that homocysteine at conce ntrations greater than or equal to 50 mu M possessed marked free radic al scavenging capacity. Finally, LDL isolated from two patients with h omozygous homocystinuria showed similar extent of Cu2+-catalyzed oxida tion as LDL from a group of healthy control subjects. Taken together, our data suggest that low concentrations of homocysteine in the presen ce of copper ions may enhance the lipid peroxidation of LDL, whereas h igh concentrations of homocysteine may protect LDL against oxidative m odification in the lipid as well as in the protein moiety. Thus, homoc ysteine-induced atherosclerosis may be explained by mechanisms other t han oxidative modification of low density lipoprotein.