Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: The possible role of nitric oxide

Toshio Hayashi, Teiji Esaki, Emiko Muto, Hatsuyo Kano, Yukako Asai, Navin Kumar Thakur, Daigo Sumi, Muthuvel Jayachandran, Akihisa Iguchi

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Abstract

Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg · kg-1 · d-1), a specific aromatase inhibitor; group 4, an HCD plus 17β-estradiol (20 μg · kg-1 · d-1); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by ≃60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that ≃50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17β-estradiol.

Original languageEnglish (US)
Pages (from-to)782-792
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume20
Issue number3
DOIs
StatePublished - Mar 2000

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Keywords

  • Aromatase
  • Atherosclerosis
  • Dehydroepiandrosterone
  • Estrogen
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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