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Research ArticleCARDIOVASCULAR

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 Jansson, Christer Westerlund, Ann-Margret Östlund-Lindqvist, Bengt Särnstrand, Håkan Bergstrand and Knut Pettersson
Journal of Pharmacology and Experimental Therapeutics October 2001, 299 (1) 76-82;
Maria Wågberg
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Anne-Heléne Jansson
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Christer Westerlund
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Ann-Margret Östlund-Lindqvist
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Bengt Särnstrand
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Håkan Bergstrand
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Knut Pettersson
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Abstract

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 ofN-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.

Footnotes

  • ↵1 Current address: AstraZeneca R&D Lund, S 221 87 Lund, Sweden.

  • ↵2 Present address: A+ Science Invest AB, P.O. Box 3096, SE-400 10 Göteborg, Sweden.

  • Abbreviations:
    LDL
    low-density lipoprotein
    WHHL
    heritable hyperlipidemic rabbit
    DiNAC
    N,N′-diacetyl-l-cystine
    CS
    contact sensitivity reaction
    DTH
    delayed type hypersensitivity reaction
    TBARS
    thiobarbituric acid-reactive substance
    NAC
    N-acetylcysteine
    Asc
    ascorbate
    • Received February 8, 2001.
    • Accepted May 17, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 299 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 299, Issue 1
1 Oct 2001
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Research ArticleCARDIOVASCULAR

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 Jansson, Christer Westerlund, Ann-Margret Östlund-Lindqvist, Bengt Särnstrand, Håkan Bergstrand and Knut Pettersson
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 76-82;

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Research ArticleCARDIOVASCULAR

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 Jansson, Christer Westerlund, Ann-Margret Östlund-Lindqvist, Bengt Särnstrand, Håkan Bergstrand and Knut Pettersson
Journal of Pharmacology and Experimental Therapeutics October 1, 2001, 299 (1) 76-82;
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