AMINOGUANIDINE HAS BOTH PROOXIDANT AND ANTIOXIDANT ACTIVITY TOWARD LDL

We previously demonstrated that aminoguanidine (AMGN) was able to prev ent oxidative modification of LDL. Initially, we thought that this occ urred solely because AMGN trapped reactive breakdown products of lipid peroxidation and prevented apoB modification, similar to AMGN's propo sed ability to trap reactive glucose intermediates and prevent advance d glycosylation end-product formation. We now demonstrate that AMGN al so displays dose-dependent pro-oxidant acid antioxidant activity towar d LDL. Moderate doses of AMGN (0.05 to 1.0 mmol/L) prevented lipid per oxidation in LDL exposed to copper. AMGN prevented the loss of polyuns aturated fatty acids and delayed or prevented conjugated-diene formati on, both of which are sensitive indicators of lipid peroxidation. The same doses of AMGN also prevented apoB modification, a step distal to lipid peroxidation, as evidenced by the ability to (1) prevent fluores cence at 420 nm, (2) block enhanced electrophoretic mobility, and (3) prevent changes leading to enhanced macrophage uptake. Thus, AMGN inhi bits LDL modification both by inhibiting lipid peroxidation as well as by trapping reactive breakdown products of lipid peroxidation. It was also demonstrated that for every LDL, there was also a very low dose of AMGN (about 0.01 mmol/L) that actually promoted lipid oxidation and subsequent protein modification. This activity of AMGN could be enhan ced by increasing the content of lipid hydroperoxide in the LDL, eg, b y aging or radioiodinating the LDL. Conversely, the pro-oxidant activi ty could be reduced by pretreatment of LDL with ebselen or vitamin E. We propose a mechanism by which AMGN effects pro-oxidant activity towa rd LDL al very low concentrations and antioxidant activity at higher c oncentrations and discuss the practical implications of these observat ions.