Vol. 299, Issue 1, 76-82, October 2001

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

Maria Wågberg, Anne-Heléne Jansson¹, Christer Westerlund, Ann-Margret Östlund-Lindqvist, Bengt Särnstrand¹, Håkan Bergstrand¹ and Knut Pettersson²

AstraZeneca R&D Mölndal, Mölndal, Sweden

Oxidation of lipoprotein-derived lipids is generally accepted to be important in atherogenesis, and lipophilic antioxidants have been suggested as potential antiatherosclerotic agents. The antiatherogenic effects observed by certain antioxidants, especially probucol, in different animal models support this suggestion. There are however also cases where other lipophilic antioxidants have not been able to support this hypothesis. This has raised the question whether the effects of probucol and similar compounds are mainly due to some other property, unrelated to their antioxidant efficacy. For example, probucol is shown to possess immunomodulatory properties. Immune reactions are known to occur during atherogenesis. We therefore tested the dimer of N-acetylcysteine, DiNAC, which is a disulfide with immunomodulating properties and enhances oxazolone-induced contact sensitivity (CS) reactions in mice, for effects on atherosclerosis. When given to male heritable hyperlipidemic rabbit (WHHL) rabbits from 10 to 22 weeks of age, this compound reduced by 50% thoracic aorta atherosclerosis (p < 0.05), without affecting 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 the CS reaction. At least one of these is also without effect on atherosclerosis in WHHL rabbits. The results show that DiNAC might represent a new treatment modality for atherosclerosis-related disease, and suggest that some antioxidants may have antiatherosclerotic properties more related to "immunomodulatory" properties than to antioxidant properties in general.