11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids thus amplifying their intracellular actions. 11β-HSD1 deficiency or inhibition, which improve metabolic syndrome and attenuate atherosclerosis in vulnerable rodent strains, is a target for drug development. However, 11β-HSD1 also converts 7-ketocholesterol (7KC) (which accumulates in fatty tissues), to the potentially more atherogenic, 7β-hydroxycholesterol. Whether atheroprotection with 11β-HSD1 deficiency is dependent on metabolism of glucocorticoids or of oxysterols is unknown.
Male atherosclerosis-prone ApoE−/− and ApoE−/−.11β-HSD1−/− double knockout (DKO) mice (11 weeks) underwent adrenalectomy (Adx) or sham surgery (n=8/group) under general anaesthesia (Isoflurane) after pre-operative analgesia (Vetergesic, 0.05 ml/30 g). Mice then received high (0.2%) cholesterol Western diet and saline (0.9%) for 12 weeks. The aorta and branches were perfusion-fixed. Lesion volume and extracellular lipids were determined by 3D optical projection tomography (OPT) and plasma and lesion lipid profiles by colorimetric assays and gas chromatography mass spectrometry.
Body/organ weights were unaltered by adrenalectomy in either genotype. Adrenalectomy in ApoE−/− mice did not alter lesion volume (232±24 vs 235±34 μm3 sham control). DKO mice had reduced lesion volumes (139±17 μm3) compared with ApoE−/− mice (P<0.05). Adrenalectomy reversed this effect (263±52 μm3). DKO mice (both sham and Adx) had increased plasma levels of 7KC (66±8 ng/ml; 83±23 DKO Adx) compared with ApoE−/− (48±8 ng/ml; 36±9 ApoE−/− Adx). Whilst aortic cholesterol levels were unchanged by adrenalectomy, aortic 7KC levels, expressed as a ratio to total plaque cholesterol, were increased in adrenalectomised DKO mice (51.2±13.8 Adx versus 14.9±3.3 sham) but remained unaltered in ApoE−/− mice (18.9±3.7 vs 16.9±3.8).
Circulating adrenal products, plausibly glucocorticoids, are therefore necessary for 11β-HSD1 deficiency to attenuate atherosclerosis. However, 11β-HSD1 deficiency increases the lipid content of plaques in the absence of glucocorticoids, perhaps due to accumulation of 7-ketocholesterol. Thus metabolism of both glucocorticoids and 7-oxysterols by 11β-HSD1 appear involved in atherogenesis.