| First Author | García RA | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 2 | Pages | e53192 |
| PubMed ID | 23383297 | Mgi Jnum | J:199430 |
| Mgi Id | MGI:5502534 | Doi | 10.1371/journal.pone.0053192 |
| Citation | Garcia RA, et al. (2013) 11beta-hydroxysteroid dehydrogenase type 1 gene knockout attenuates atherosclerosis and in vivo foam cell formation in hyperlipidemic apoE(-)/(-) mice. PLoS One 8(2):e53192 |
| abstractText | BACKGROUND: Chronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11betaHSD1 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 11betaHSD1 in atherogenesis, 11betaHSD1 knockout mice were created on the pro-atherogenic apoE(-)/(-) background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50% in 11betaHSD1(-)/(-)/apoE(-)/(-) mice vs. 11betaHSD1(+)/(+)/apoE(-)/(-) mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40% in 11betaHSD1(-)/(-)/apoE(-)/(-) mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced approximately 30% in 11betaHSD1(-)/(-)/apoE(-)/(-)mice. Bone marrow transplantation from 11betaHSD1(-)/(-)/apoE(-)/(-) mice into apoE(-)/(-) recipients reduced plaque area 39-46% in the thoracic aorta. In vivo foam cell formation was evaluated in thioglycollate-elicited peritoneal macrophages from 11betaHSD1(+)/(+)/apoE(-)/(-) and 11betaHSD1(-)/(-)/apoE(-)/(-) mice fed a Western diet for approximately 5 weeks. Foam cell cholesterol levels were reduced 48% in 11betaHSD1(-)/(-)/apoE(-)/(-) mice vs. control. Microarray profiling of peritoneal macrophages revealed differential expression of genes involved in inflammation, stress response and energy metabolism. Several toll-like receptors (TLRs) were downregulated in 11betaHSD1(-)/(-)/apoE(-)/(-) mice including TLR 1, 3 and 4. Cytokine release from 11betaHSD1(-)/(-)/apoE(-)/(-)-derived peritoneal foam cells was attenuated following challenge with oxidized LDL. CONCLUSIONS: These findings suggest that 11betaHSD1 inhibition may have the potential to limit plaque development at the vessel wall and regulate foam cell formation independent of changes in plasma lipids. The diminished cytokine response to oxidized LDL stimulation is consistent with the reduction in TLR expression and suggests involvement of 11betaHSD1 in modulating binding of pro-atherogenic TLR ligands. |
