Aminoguanidine inhibits oxidative modification of low density lipoprotein protein and the subsequent increase in uptake by macrophage scavenger receptors.
Aminoguanidine decreases the formation of advanced glycosylation end products that occurs during chronic hyperglycemia. Presumably this occurs because early glycosylation products preferentially bind to aminoguanidine rather than to lysine groups of adjacent proteins. Because oxidative modification of low density lipoprotein (LDL) also involves derivatization of lysine residues of apolipoprotein (apo) B by reactive aldehydes formed during the decomposition of oxidized fatty acids, we postulated that aminoguanidine might also inhibit the oxidatively induced modification of LDL protein. To test this hypothesis we oxidized LDL by incubation with Cu2+ or with endothelial cells in the absence or presence of aminoguanidine. Aminoguanidine prevented apo B lysine modification, as measured by fluorescence spectroscopy, and inhibited in a dose-dependent manner the oxidatively induced increase in subsequent macrophage uptake. At concentrations that inhibited apo B modification (5-10 mM), aminoguanidine increased the lag time in diene conjugation but did not affect the plateau value reached. These data indicate that aminoguanidine inhibits oxidative modification of LDL protein in large part by binding reactive aldehydes formed during lipid peroxidation and preventing their subsequent conjugation to apo B. Thus, aminoguanidine (and related compounds) may be of dual benefit in inhibiting atherosclerosis, both by inhibiting formation of advanced glycosylation end products and by inhibiting the modification of LDL apo B that makes it a ligand for scavenger receptors.
Picard
S
S
Department of Medicine, University of California, San Diego, La Jolla 92093-0613.
Parthasarathy
S
S
Fruebis
J
J
Witztum
J L
JL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D013053:Spectrophotometry
D000975:Antioxidants; D006146:Guanidines; D008077:Lipoproteins, LDL; C004479:pimagedine