title: 11β-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe-/- mice.
abstract: Mineralocorticoid receptor (MR) activation is proinflammatory and proatherogenic. Antagonism of MR improves survival in humans with congestive heart failure caused by atherosclerotic disease. In animal models, activation of MR exacerbates atherosclerosis. The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) prevents inappropriate activation of the MR by inactivating glucocorticoids in mineralocorticoid-target tissues. To determine whether glucocorticoid-mediated activation of MR increases atheromatous plaque formation, we generated Apoe(-/-)/11β-HSD2(-/-) double-knockout (E/b2) mice. On chow diet, E/b2 mice developed atherosclerotic lesions by 3 months of age, whereas Apolipoprotein E (Apoe(-/-)) mice remained lesion free. Brachiocephalic plaques in 3-month-old E/b2 mice showed increased macrophage and lipid content and reduced collagen content compared with similar sized brachiocephalic plaques in 6-month-old Apoe(-/-) mice. Crucially, treatment of E/b2 mice with eplerenone, an MR antagonist, reduced plaque development and macrophage infiltration while increasing collagen and smooth muscle cell content without any effect on systolic blood pressure. In contrast, reduction of systolic blood pressure in E/b2 mice using the epithelial sodium channel blocker amiloride produced a less-profound atheroprotective effect. Vascular cell adhesion molecule 1 expression was increased in the endothelium of E/b2 mice compared with Apoe(-/-) mice. Similarly, aldosterone increased vascular cell adhesion molecule 1 expression in mouse aortic endothelial cells, an effect mimicked by corticosterone only in the presence of an 11β-HSD2 inhibitor. Thus, loss of 11β-HSD2 leads to striking atherogenesis associated with activation of MR, stimulating proinflammatory processes in the endothelium of E/b2 mice.
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Graeme A
authors.initials: GA
authors.lastname: Deuchar
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Danielle
authors.initials: D
authors.lastname: McLean
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Patrick W F
authors.initials: PWF
authors.lastname: Hadoke
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: David G
authors.initials: DG
authors.lastname: Brownstein
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Chapman
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.affiliation: Centre for Cardiovascular Science, The Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
authors.forename: Yuri V
authors.initials: YV
authors.lastname: Kotelevtsev
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000235:genetics / Q000378:metabolism*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D000077545:Eplerenone; D015971:Gene Expression Regulation, Enzymologic; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D000451:Mineralocorticoid Receptor Antagonists; D026941:Sodium Channel Blockers; D013148:Spironolactone; D000077545:Eplerenone; D000584:Amiloride; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2