title: Modulation of 11β-hydroxysteroid dehydrogenase as a strategy to reduce vascular inflammation.
abstract: Atherosclerosis is a chronic inflammatory disease in which initial vascular damage leads to extensive macrophage and lymphocyte infiltration. Although acutely glucocorticoids suppress inflammation, chronic glucocorticoid excess worsens atherosclerosis, possibly by exacerbating systemic cardiovascular risk factors. However, glucocorticoid action within the lesion may reduce neointimal proliferation and inflammation. Glucocorticoid levels within cells do not necessarily reflect circulating levels due to pre-receptor metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSDs). 11β-HSD2 converts active glucocorticoids into inert 11-keto forms. 11β-HSD1 catalyses the reverse reaction, regenerating active glucocorticoids. 11β-HSD2-deficiency/inhibition causes hypertension, whereas deficiency/inhibition of 11β-HSD1 generates a cardioprotective lipid profile and improves glycemic control. Importantly, 11β-HSD1-deficiency/inhibition is atheroprotective, whereas 11β-HSD2-deficiency accelerates atherosclerosis. These effects are largely independent of systemic risk factors, reflecting modulation of glucocorticoid action and inflammation within the vasculature. Here, we consider whether evidence linking the 11β-HSDs to vascular inflammation suggests these isozymes are potential therapeutic targets in vascular injury and atherosclerosis.
authors.affiliation: University/ BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. Patrick.Hadoke@ed.ac.uk
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.forename: Tiina
authors.initials: T
authors.lastname: Kipari
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Karen E
authors.initials: KE
authors.lastname: Chapman
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000276:immunology / Q000502:physiology*; D050197:Atherosclerosis / Q000150:complications / Q000201:enzymology / Q000276:immunology*; D005938:Glucocorticoids / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D058426:Neointima / Q000276:immunology; D014657:Vasculitis / Q000150:complications / Q000201:enzymology / Q000276:immunology*
chemical_list: D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2