N,N '-diacetyl-L-cystine (DiNAC), the disulphide dimer of N-acetylcysteine, inhibits atherosclerosis in WHHL rabbits: Evidence for immunomodulatory agents as a new approach to prevent atherosclerosis

Oxidation of lipoprotein-derived lipids is generally accepted to be importa nt in atherogenesis, and lipophilic antioxidants have been suggested as pot ential antiatherosclerotic agents. The antiatherogenic effects observed by certain antioxidants, especially probucol, in different animal models suppo rt this suggestion. There are however also cases where other lipophilic ant ioxidants have not been able to support this hypothesis. This has raised th e question whether the effects of probucol and similar compounds are mainly due to some other property, unrelated to their antioxidant efficacy. For e xample, probucol is shown to possess immunomodulatory properties. Immune re actions are known to occur during atherogenesis. We therefore tested the di mer of N-acetylcysteine, DiNAC, which is a disulfide with immunomodulating properties and enhances oxazolone-induced contact sensitivity (CS) reaction s in mice, for effects on atherosclerosis. When given to male heritable hyp erlipidemic rabbit (WHHL) rabbits from 10 to 22 weeks of age, this compound reduced by 50% thoracic aorta atherosclerosis (p < 0.05), without affectin g plasma lipid levels. Here we also show that probucol and a close chemical analog, both known to prevent atherosclerosis in WHHL rabbits, enhance the CS reaction in mice, while two other related antioxidants did not affect t he CS reaction. At least one of these is also without effect on atheroscler osis in WHHL rabbits. The results show that DiNAC might represent a new tre atment modality for atherosclerosis-related disease, and suggest that some antioxidants may have antiatherosclerotic properties more related to "immun omodulatory" properties than to antioxidant properties in general.