Paradoxical protective effect of aminoguanidine toward low-density lipoprotein oxidation: inhibition of apolipoprotein B fragmentation without preventing its carbonylation. Mechanism of action of aminoguanidine.
Oxidative modification of low-density lipoproteins (LDLs) is an important feature in the initiation and progression of atherosclerosis. Aminoguanidine (AMG), classically described as an inhibitor of advanced glycation end products, turned out to be also efficient in animal models as an antioxidant against lipid peroxidation. The originality of the present study was based on the simultaneous assessment of the oxidation of LDL lipid and protein moieties in order to characterize the molecular sites of AMG protection. Oxidation of the LDL lipid moiety was monitored by measuring conjugated dienes (CD) and hydroperoxide molecular species from cholesteryl esters (CEOOH) and phosphatidylcholines (PCOOH). LDL protein oxidative modifications were assessed by evaluating apoB carbonylation and fragmentation. The LDL oxidation was mediated by water gamma radiolysis, which has the advantage of being quantitative and highly selective with regard to the free radicals produced. Here, we reported that AMG resulted in a protection of LDLs against lipid peroxidation (both in the lag phase and in the propagation phase) and against apoB fragmentation in a concentration-dependent manner, due to the scavenging effect of AMG toward lipid peroxyl radicals. Paradoxically, AMG was poorly efficient against apoB carbonylation that began during the lag phase. We hypothesize that, even in the presence of AMG, a nonnegligible proportion of (*)OH radicals remained able to initiate oxidation of the LDL protein moiety, leading to apoB carbonylation.
D000466:Alkadienes / Q000032:analysis / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects; D002788:Cholesterol Esters / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005720:Gamma Rays; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis; D015151:Immunoblotting; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000528:radiation effects; D008077:Lipoproteins, LDL / Q000737:chemistry* / Q000378:metabolism / Q000528:radiation effects; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects; D010713:Phosphatidylcholines / Q000737:chemistry; D014867:Water / Q000737:chemistry
D000466:Alkadienes; D000975:Antioxidants; D001055:Apolipoproteins B; D002788:Cholesterol Esters; D006146:Guanidines; D008077:Lipoproteins, LDL; D010446:Peptide Fragments; D010713:Phosphatidylcholines; D014867:Water; D006861:Hydrogen Peroxide; C004479:pimagedine