title: 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice.
abstract: The enzyme 11beta-hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11beta-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11beta-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11beta-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11beta-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.
authors.affiliation: Merck Research Laboratories, Merck and Company, Rahway, NJ 07065, USA. anne_vosatka@merck.com
authors.forename: Anne
authors.initials: A
authors.lastname: Hermanowski-Vosatka
authors.forename: James M
authors.initials: JM
authors.lastname: Balkovec
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chen
authors.forename: Melba
authors.initials: M
authors.lastname: Hernandez
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Koo
authors.forename: Cheryl B
authors.initials: CB
authors.lastname: Le Grand
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Li
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.forename: Steven S
authors.initials: SS
authors.lastname: Mundt
authors.forename: Heather
authors.initials: H
authors.lastname: Noonan
authors.forename: Christian N
authors.initials: CN
authors.lastname: Nunes
authors.forename: Steven H
authors.initials: SH
authors.lastname: Olson
authors.forename: Bill
authors.initials: B
authors.lastname: Pikounis
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.forename: Nancy
authors.initials: N
authors.lastname: Robertson
authors.forename: James M
authors.initials: JM
authors.lastname: Schaeffer
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Martin S
authors.initials: MS
authors.lastname: Springer
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Matthias
authors.initials: M
authors.lastname: Strowski
authors.forename: Kenneth
authors.initials: K
authors.lastname: Wu
authors.forename: Tsueiju
authors.initials: T
authors.lastname: Wu
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: Rolf
authors.initials: R
authors.lastname: Thieringer
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D001381:Azepines / Q000008:administration & dosage*; D001786:Blood Glucose / Q000187:drug effects; D003348:Cortisone / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005227:Fatty Acids / Q000097:blood; D006854:Hydrocortisone; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D013577:Syndrome; D014230:Triazoles / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood
chemical_list: C505014:3-(1-adamantyl)-6,7,8,9-tetrahydro-5H-(1,2,4)triazolo(4,3-a)azepine; D001381:Azepines; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D007328:Insulin; D014230:Triazoles; D014280:Triglycerides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000218:Adamantane; D003348:Cortisone; D006854:Hydrocortisone