11β-Hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe -/- mice

Graeme A. Deuchar, Danielle McLean, Patrick W F Hadoke, David G. Brownstein, David J. Webb, John Mullins, Karen Chapman, Jonathan R. Seckl, Yuri V. Kotelevtsev

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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 MRincreases atheromatous plaque formation,wegenerated 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, anMRantagonist, 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 ofan11β-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.

Original languageEnglish
Pages (from-to)236-246
Number of pages11
JournalEndocrinology
Volume152
Issue number1
DOIs
Publication statusPublished - Jan 2011
Externally publishedYes

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Deuchar, G. A., McLean, D., Hadoke, P. W. F., Brownstein, D. G., Webb, D. J., Mullins, J., ... Kotelevtsev, Y. V. (2011). 11β-Hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe -/- mice. Endocrinology, 152(1), 236-246. https://doi.org/10.1210/en.2010-0925