11b-Hydroxysteroid Dehydrogenase Type 1 Gene Knockout Attenuates Atherosclerosis and In Vivo Foam Cell Formation in Hyperlipidemic apoE2/2 Mice

Background: Chronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11b-hydroxysteroid dehydrogenase type 1 (11bHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11bHSD1 has been shown to reduce atherosclerosis in murine models. However, the cellular and molecular details for this effect have not been elucidated. Methodology/Principal Findings: To examine the role of 11bHSD1 in atherogenesis, 11bHSD1 knockout mice were created on the pro-atherogenic apoE2/2 background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50 % in 11bHSD12/2/apoE2/2 mice vs. 11bHSD1+/+/apoE2/2 mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40 % in 11bHSD12/2/apoE2/2 mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced,30 % in 11bHSD12/2/apoE2/2 mice. Bone marrow transplantation fro