Aminoguanidine has both pro-oxidant and antioxidant activity toward LDL.
We previously demonstrated that aminoguanidine (AMGN) was able to prevent oxidative modification of LDL. Initially, we thought that this occurred solely because AMGN trapped reactive breakdown products of lipid peroxidation and prevented apoB modification, similar to AMGN's proposed ability to trap reactive glucose intermediates and prevent advanced glycosylation end-product formation. We now demonstrate that AMGN also displays dose-dependent pro-oxidant and antioxidant activity toward LDL. Moderate doses of AMGN (0.05 to 1.0 mmol/L) prevented lipid peroxidation in LDL exposed to copper. AMGN prevented the loss of polyunsaturated fatty acids and delayed or prevented conjugated-diene formation, 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 fluorescence at 420 nm, (2) block enhanced electrophoretic mobility, and (3) prevent changes leading to enhanced macrophage uptake. Thus, AMGN inhibits 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 enhanced by increasing the content of lipid hydroperoxide in the LDL, eg, by aging or radioiodinating the LDL. Conversely, the pro-oxidant activity could be reduced by pretreatment of LDL with ebselen or vitamin E. We propose a mechanism by which AMGN effects pro-oxidant activity toward LDL at very low concentrations and antioxidant activity at higher concentrations and discuss the practical implications of these observations.
Philis-Tsimikas
A
A
Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Parthasarathy
S
S
Picard
S
S
Palinski
W
W
Witztum
J L
JL
D000975:Antioxidants / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D008054:Lipid Peroxides / Q000037:antagonists & inhibitors; D008077:Lipoproteins, LDL / Q000145:classification / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects
D000975:Antioxidants; D001055:Apolipoproteins B; D006146:Guanidines; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; C004479:pimagedine