title: 11β-HSD1 inhibition reduces atherosclerosis in mice by altering proinflammatory gene expression in the vasculature.
abstract: 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is implicated in the etiology of metabolic syndrome. We previously showed that pharmacological inhibition of 11β-HSD1 ameliorated multiple facets of metabolic syndrome and attenuated atherosclerosis in ApoE-/- mice. However, the molecular mechanism underlying the atheroprotective effect was not clear. In this study, we tested whether and how 11β-HSD1 inhibition affects vascular inflammation, a major culprit for atherosclerosis and its associated complications. ApoE-/- mice were treated with an 11β-HSD1 inhibitor for various periods of time. Plasma lipids and aortic cholesterol accumulation were quantified. Several microarray studies were carried out to examine the effect of 11β-HSD1 inhibition on gene expression in atherosclerotic tissues. Our data suggest 11β-HSD1 inhibition can directly modulate atherosclerotic plaques and attenuate atherosclerosis independently of lipid lowering effects. We identified immune response genes as the category of mRNA most significantly suppressed by 11β-HSD1 inhibition. This anti-inflammatory effect was further confirmed in plaque macrophages and smooth muscle cells procured by laser capture microdissection. These findings in the vascular wall were corroborated by reduction in circulating MCP1 levels after 11β-HSD1 inhibition. Taken together, our data suggest 11β-HSD1 inhibition regulates proinflammatory gene expression in atherosclerotic tissues of ApoE-/- mice, and this effect may contribute to the attenuation of atherosclerosis in these animals.
authors.affiliation: Cardiovascular Disease Department, Merck Research Laboratories, Rahway, NJ, USA.
authors.forename: Mingjuan J
authors.initials: MJ
authors.lastname: Luo
authors.forename: Rolf
authors.initials: R
authors.lastname: Thieringer
authors.forename: Martin S
authors.initials: MS
authors.lastname: Springer
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: Anne
authors.initials: A
authors.lastname: Hermanowski-Vosatka
authors.forename: Andrew
authors.initials: A
authors.lastname: Plump
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Gloria J
authors.initials: GJ
authors.lastname: Ding
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Kawka
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Koo
authors.forename: Cheryl B Le
authors.initials: CB
authors.lastname: Grand
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.forename: Milana M
authors.initials: MM
authors.lastname: Maletic
authors.forename: Lorraine
authors.initials: L
authors.lastname: Malkowitz
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Irwin
authors.initials: I
authors.lastname: Singer
authors.forename: Sherman T
authors.initials: ST
authors.lastname: Waddell
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Yuan
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Serguei
authors.initials: S
authors.lastname: Stepaniants
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.forename: Pek Yee
authors.initials: PY
authors.lastname: Lum
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Wang
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology; D002784:Cholesterol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D005802:Genes, MHC Class II / Q000235:genetics; D005938:Glucocorticoids / Q000378:metabolism; D061346:Laser Capture Microdissection; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D014657:Vasculitis / Q000150:complications / Q000188:drug therapy*
chemical_list: D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D008055:Lipids; D002784:Cholesterol; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1