11β-Hydroxysteroid Dehydrogenase Type 1 Gene Knockout Attenuates Atherosclerosis and In Vivo Foam Cell Formation in Hyperlipidemic apoE−/− Mice

Abstract

BackgroundChronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11βHSD1 has been shown to reduce atherosclerosis in murine models. However, the cellular and molecular details for this effect have not been elucidated.Methodology/Principal FindingsTo examine the role of 11βHSD1 in atherogenesis, 11βHSD1 knockout mice were created on the pro-atherogenic apoE−/− background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50% in 11βHSD1−/−/apoE−/− mice vs. 11βHSD1+/+/apoE−/− mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40% in 11βHSD1−/−/apoE−/− mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced ∼30% in 11βHSD1−/−/apoE−/− mice. Bone marrow transplantation from 11βHSD1−/−/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 11βHSD1+/+/apoE−/− and 11βHSD1−/−/apoE−/− mice fed a Western diet for ∼5 weeks. Foam cell cholesterol levels were reduced 48% in 11βHSD1−/−/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 11βHSD1−/−/apoE−/− mice including TLR 1, 3 and 4. Cytokine release from 11βHSD1−/−/apoE−/−-derived peritoneal foam cells was attenuated following challenge with oxidized LDL.ConclusionsThese findings suggest that 11βHSD1 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 11βHSD1 in modulating binding of pro-atherogenic TLR ligands.

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

“…Diet‐induced atherosclerosis in mice was performed as described previously (Chiba et al ., 2008; Usui et al ., 2012; García et al ., 2013). Briefly, male ApoE (−/−) and ApoE (−/−) / Vash1 (−/−) mice were fed a HFD (D12079B, Research Diets, Inc., New Brunswick, NJ, USA) for 12 weeks starting from 8 weeks of age.…”

Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

“…In a preclinical model of atherosclerosis in ApoE-deficient mice, pharmacological inhibition (Hermanowski-Vosatka et al 2005), or genetic ablation (Garcia et al 2013, Kipari et al 2013), of 11β-HSD1 is associated with reduction in plaque size independently of changes in lipid availability. Plaque size reduction in ApoE/11β-HSD1 double knockout mice was attributed to loss of 11β-HSD1 in bone marrow-derived cells (Kipari et al 2013).…”

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

“…Following potential beneficial effects observed in animal models [94], the influence of 11βHSD1 on liver fat accumulation and progression of nonalcoholic fatty liver disease deserves more detailed investigation. Both knockout of 11βHSD1 and treatment with 11βHSD1 inhibitors attenuates atherosclerosis in ApoE −/− mice [18,95]. It seems that this effect is independent of improvements in other metabolic variables such as blood lipids and insulin resistance, since it can be recapitulated by adoptive transfer of 11βHSD1-deficient bone marrow cells [18].…”