ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 25 P156

Attenuated atherosclerosis in 11[beta]-hydroxysteroid dehydrogenase type 1 deficient ApoE-/- mice is associated with reduced aortic VCAM-1 expression and reduced MCP-1 in the visceral fat

Tiina Kipari, Tak-Yung Man, Patrick Hadoke, John Savill, Karen Chapman & Jonathan Seckl

University of Edinburgh, Edinburgh, UK.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates glucocorticoids in intact cells, converting inert cortisone into active cortisol. We have previously shown attenuated atherosclerosis development, reduced plasma monocyte chemoattractant protein-1 (MCP-1) and reduced macrophage/T cell infiltration within atherosclerotic lesions in 11β-HSD1−/−×ApoE−/− double knock-out (DKO) mice fed western diet (WD).

To determine the mechanism responsible for reduced inflammatory cell infiltration, we analysed gene expression by real-time PCR in the ascending aorta for MCP-1 and adhesion molecules. Aortic MCP-1 mRNA levels were increased by WD, but there was no difference by genotype (DKO 1.34±0.19; ApoE−/− 1.31±0.29, P=0.95), suggesting that differences in aortic MCP-1 expression did not underline the reduced macrophage recruitment in WD fed DKO mice. Aortic vascular cell adhesion molecule-1 (VCAM-1) mRNA expression was significantly lower in DKO mice fed WD (DKO 0.69±0.10; ApoE−/− 1.08±0.09, P<0.05), suggesting reduced inflammatory cell adhesion. This was specific to VCAM-1, since aortic inter-cellular adhesion molecule-1 (ICAM-1) mRNA levels were unaffected by 11β-HSD1-deficiency (DKO 1.09±0.08; ApoE−/− 1.19±0.05, P=0.33).

To investigate inflammation beyond the arterial wall, we measured the levels of adipocytokines and cytokines in the mesenteric adipose tissue (MesAT, i.e. visceral fat). Chow fed DKO mice exhibited increased leptin mRNA expression in MesAT (DKO 0.85±0.20; ApoE−/− 0.25±0.07, P<0.01), but following WD there was no difference by genotype (DKO WD 1.27±0.38; ApoE−/− WD 1.24±0.23, P=0.95). MesAT expression of 11β-HSD1 was down-regulated in WD fed ApoE KO mice (ApoE−/− WD 0.97±0.19; ApoE−/− chow 2.31±0.47, P<0.01). Lastly MCP-1 mRNA expression and interleukin 6 (IL6) in the MesAT was lower in WD fed DKO mice (MCP1:DKO 0.56±0.08; ApoE−/− 1.43±0.36, P<0.05, IL6/: DKO 0.44±0.03; ApoE−/− 0.68±0.13, P<0.05.

In conclusion atheroprotection in 11β-HSD1 deficiency is plausibly via reduced adhesion of monocytes and lymphocytes to the endothelium, whereas reduced inflammation in visceral fat is via reduced local chemoattraction. This highlights tissue-specific changes in inflammation with 11β-HSD1 deficiency.

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