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.
Bottom Line: Incubation (4-24 h) of aortic rings with either 7-KC (25 μM) or 7βOHC (20 μM) had no effect on endothelium-dependent (acetylcholine) or -independent (sodium nitroprusside) relaxation.These results demonstrate that 7-KC has greater effects than 7βOHC on vascular function, and that 11β-HSD1 can inter-convert 7-KC and 7βOHC 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 11β-HSD1 inhibitors.
Affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, College of Medicine and Veterinary Medicine, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, Scotland, UK.Show MeSH
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Mentions: As expected , glucocorticoids were inter-converted by incubation with intact mouse aortic rings. The velocity of reduction of 11-dehydrocorticosterone to corticosterone (Fig. 3A) proceeded considerably (∼10×) faster than the dehydrogenation of corticosterone to 11-dehydrocorticosterone. Reduction of 11-dehydrocorticosterone was attenuated in mice lacking 11β-HSD1, whereas deletion of this enzyme produced only a small (though significant) increase in the dehydrogenation of corticosterone (to 11-dehydrocorticosterone) (Fig. 3A). The oxysterols 7-KC and 7βOHC were also inter-converted by incubation with intact mouse aortic rings. In contrast to glucocorticoids, however, the velocities of reduction of 7-KC (to 7βOHC) and of dehydrogenation of 7βOHC (to 7-KC) were similar following incubation with mouse aortic rings (Fig. 3B). Genetic disruption of Hsd11b1 significantly reduced the velocity of conversion of both 7-KC and 7βOHC (Fig. 3B), with 96 ± 6% of added substrates being recovered. 7-KC was not inter-converted with 7αOHC in aortic rings (data not shown).
Affiliation: Endocrinology Unit, University/BHF Centre for Cardiovascular Science, College of Medicine and Veterinary Medicine, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, Scotland, UK.