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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.

Mitić T, Andrew R, Walker BR, Hadoke PW - Biochimie (2012)

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.

View Article: PubMed Central - PubMed

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.

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11β-HSD1 catalyses reduction of 7-Ketocholesterol (7-KC) and dehydrogenation of 7β-Hydroxycholesterol (7βOHC) in isolated mouse aorta. Incubation with mouse aortic rings (24 h; 37 °C; 5% CO2) resulted in (A) metabolism of glucocorticoids (n = 10); reduction of 11-dehydrocorticosterone (11DHC; 30 nM) to form corticosterone (Cort) was reduced, but not abolished, in aortae from 11β-HSD1−/− mice. Low levels of dehydrogenation of Cort (30 nM; to form 11DHC) were detected in mouse aorta. Surprisingly this was slightly (but significantly) increased in the absence of 11β-HSD1. (B) Both 7-oxysterols (1 μM) were metabolized following exposure to mouse aortic rings (n = 6) but, in contrast to glucocorticoids, both dehydrogenation (conversion of 7βOHC to 7-KC) and reduction (7-KC to 7βOHC) reactions were virtually abolished in arteries lacking 11β-HSD1 (11β-HSD1−/−). Data are mean ± SEM, and were compared using unpaired Student's t-test, **p < 0.01, ***p < 0.001 vs velocity of the same reaction in tissues from C57Bl/6 mice.
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fig3: 11β-HSD1 catalyses reduction of 7-Ketocholesterol (7-KC) and dehydrogenation of 7β-Hydroxycholesterol (7βOHC) in isolated mouse aorta. Incubation with mouse aortic rings (24 h; 37 °C; 5% CO2) resulted in (A) metabolism of glucocorticoids (n = 10); reduction of 11-dehydrocorticosterone (11DHC; 30 nM) to form corticosterone (Cort) was reduced, but not abolished, in aortae from 11β-HSD1−/− mice. Low levels of dehydrogenation of Cort (30 nM; to form 11DHC) were detected in mouse aorta. Surprisingly this was slightly (but significantly) increased in the absence of 11β-HSD1. (B) Both 7-oxysterols (1 μM) were metabolized following exposure to mouse aortic rings (n = 6) but, in contrast to glucocorticoids, both dehydrogenation (conversion of 7βOHC to 7-KC) and reduction (7-KC to 7βOHC) reactions were virtually abolished in arteries lacking 11β-HSD1 (11β-HSD1−/−). Data are mean ± SEM, and were compared using unpaired Student's t-test, **p < 0.01, ***p < 0.001 vs velocity of the same reaction in tissues from C57Bl/6 mice.

Mentions: As expected [15], 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).


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.

Mitić T, Andrew R, Walker BR, Hadoke PW - Biochimie (2012)

11β-HSD1 catalyses reduction of 7-Ketocholesterol (7-KC) and dehydrogenation of 7β-Hydroxycholesterol (7βOHC) in isolated mouse aorta. Incubation with mouse aortic rings (24 h; 37 °C; 5% CO2) resulted in (A) metabolism of glucocorticoids (n = 10); reduction of 11-dehydrocorticosterone (11DHC; 30 nM) to form corticosterone (Cort) was reduced, but not abolished, in aortae from 11β-HSD1−/− mice. Low levels of dehydrogenation of Cort (30 nM; to form 11DHC) were detected in mouse aorta. Surprisingly this was slightly (but significantly) increased in the absence of 11β-HSD1. (B) Both 7-oxysterols (1 μM) were metabolized following exposure to mouse aortic rings (n = 6) but, in contrast to glucocorticoids, both dehydrogenation (conversion of 7βOHC to 7-KC) and reduction (7-KC to 7βOHC) reactions were virtually abolished in arteries lacking 11β-HSD1 (11β-HSD1−/−). Data are mean ± SEM, and were compared using unpaired Student's t-test, **p < 0.01, ***p < 0.001 vs velocity of the same reaction in tissues from C57Bl/6 mice.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585959&req=5

fig3: 11β-HSD1 catalyses reduction of 7-Ketocholesterol (7-KC) and dehydrogenation of 7β-Hydroxycholesterol (7βOHC) in isolated mouse aorta. Incubation with mouse aortic rings (24 h; 37 °C; 5% CO2) resulted in (A) metabolism of glucocorticoids (n = 10); reduction of 11-dehydrocorticosterone (11DHC; 30 nM) to form corticosterone (Cort) was reduced, but not abolished, in aortae from 11β-HSD1−/− mice. Low levels of dehydrogenation of Cort (30 nM; to form 11DHC) were detected in mouse aorta. Surprisingly this was slightly (but significantly) increased in the absence of 11β-HSD1. (B) Both 7-oxysterols (1 μM) were metabolized following exposure to mouse aortic rings (n = 6) but, in contrast to glucocorticoids, both dehydrogenation (conversion of 7βOHC to 7-KC) and reduction (7-KC to 7βOHC) reactions were virtually abolished in arteries lacking 11β-HSD1 (11β-HSD1−/−). Data are mean ± SEM, and were compared using unpaired Student's t-test, **p < 0.01, ***p < 0.001 vs velocity of the same reaction in tissues from C57Bl/6 mice.
Mentions: As expected [15], 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).

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus