Endocrine Abstracts

Recent investigations have suggested that 11ß-hydroxysteroid dehydrogenase-1 (11ßHSD1) activity influences development of atherosclerotic lesions and that pharmacological inhibition of this enzyme may have therapeutic benefits. Whilst these findings have been attributed to glucocorticoid metabolism, 11ßHSD1 also inter-converts 7-oxysterols (oxidized products of cholesterol which may promote atherogenesis). This study investigates whether metabolism of 7-oxysterols within the vessel wall influences 7-oxysterol-induced vascular dysfunction.

Circulating concentrations of 7-oxysterols were determined by GC/MS in plasma of C57Bl6 mice (male, 16 weeks, n=14). Metabolism of 7-oxysterols by 11βHSD1 was assessed ex vivo in thoracic aortae from C57Bl6 and 11ßHSD1^−/− mice, as inter-conversion of 7ß-hydroxycholesterol (7ßOHC) and 7-ketocholesterol (7KC). The influence of prolonged incubation (2–24 h) with 7-oxysterols (20–25 nM) on aortic function (C57Bl6, n=6–8) was assessed using wire myography. Data are mean±S.E.M.

7-Oxysterols were detected in the circulation of C57Bl6 mice (7KC=91±22 nM; 7ßOHC=23±5.2 nM). Aortic 11ßHSD1 inter-converted 7-oxysterols, with preference for dehydrogenation of 7ßOHC (deh: 410±30 vs red: 278±80 pmol/mg per day). Unlike glucocorticoids, inter-conversion of 7-oxysterols was not catalyzed by vascular 11ßHSD2, as demonstrated by lack of metabolism in aortae from 11ßHSD1^−/− mice. Prolonged incubation with 7-KC had no effect on aortic contraction in response to 5-hydroxytryptamine or potassium chloride; a trend towards reduced noradrenergic contraction (E_max (mN/mm) control 2.4±0.4 vs 1.56±0.5) was not significant. Similarly endothelium-dependent (acetylcholine; E_max (%) control 66.9±43.5 vs 75.4±6.4); and -independent (SNP; data not shown) relaxations were unaltered after exposure to 7-KCl. Similar results were obtained with 7ßOHC.

These results support a role for local vascular 11ßHSD1 in oxidizing circulatory 7ßOHC. Although these data suggest that concentrations generated are unlikely to cause vascular dysfunction, metabolism of oxysterols by 11ßHSD1 may influence vascular lesion development, and oxysterols may also compete with glucocorticoids for 11ßHSD1.