11β-Hydroxysteroid dehydrogenase type 1 contributes to the regulation of 7-oxysterol levels in the arterial wall through the inter-conversion of 7-ketocholesterol and 7β-hydroxycholesterol

The atherogenic 7-oxysterols, 7-ketocholesterol (7-KC) and 7 beta-hydroxycholesterol (7 beta OHC), can directly impair arterial function. Inter-conversion of 7-KC and 7f3OHC has recently been shown as a novel role for the glucocorticoid-metabolizing enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1). Since this enzyme is expressed in vascular smooth muscle cells, we addressed the hypothesis that interconversion of 7-KC and 7 beta OHC by 11 beta-HSD1 may contribute to regulation of arterial function. Incubation (4-24 h) of aortic rings with either 7-KC (25 mu M) or 7 beta OHC (20 mu M) had no effect on endothelium-dependent (acetylcholine) or -independent (sodium nitroprusside) relaxation. In contrast, exposure to 7-KC (but not to 7 beta OHC) attenuated noradrenaline-induced contraction (E-max) after 4 h (0.78 +/- 0.28 vs 0.40 +/- 0.08 mN/mm; p < 0.05) and 24 h (2.28 +/- 0.34 vs 1.56 +/- 0.48 mN/mm; p < 0.05). Both 7-oxysterols were detected by GCMS in the aortic wall of chow-fed C57BI6/J mice, with concentrations of 7-KC (1.41 +/- 0.81 ng/mg) higher (p = 0.05) than 7 beta OHC (0.16 +/- 0.06 ng/mg). In isolated mouse aortic rings 11 beta-HSD1 was shown to act as an oxo-reductase, inter-converting 7-KC and 7 beta OHC. This activity was lost in aorta from 11 beta-HSD1(-/-)mice, which had low oxysterol levels. Renal homogenates from 11 beta-HSD1(-/-)mice were used to confirm that the type 2 isozyme of 11 beta-HSD does not inter-convert 7-KC and 7 beta OHC. These results demonstrate that 7-KC has greater effects than 7 beta OHC on vascular function, and that 11 beta-HSD1 can inter-convert 7-KC and 7 beta OHC in the arterial wall, contributing to the regulation of 7-oxysterol levels and potentially influencing vascular function. This mechanism may be important in the cardioprotective effects of 11 beta-HSD1 inhibitors. (C) 2012 Elsevier Masson SAS. All rights reserved.