SFEBES2009 Poster Presentations Diabetes and metabolism (59 abstracts)
University of Edinburgh, Edinburgh, UK.
High plasma levels of glucocorticoids cause metabolic disease (central obesity, hypertension, diabetes) and increase risk of cardiovascular disease. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates glucocorticoids in intact cells, converting inert cortisone (11-dehydrocorticosterone in rodents) into active cortisol (corticosterone in rodents). Recent work has shown the pathological importance of elevated adipose tissue 11β-HSD1 expression in development of obesity, potentially driving metabolic disease and 11β-HSD1 deficiency or inhibition ameliorates type II diabetes and obesity-related disease in humans and animal models. Importantly, 11β-HSD1 inhibition prevents atherosclerotic plaque development in atherosclerosis-prone ApoE−/− mice fed a western diet (WD).
We have recently shown substantially reduced atherosclerotic lesion development in 11β-HSD1−/−ApoE−/− double knock-out (DKO) mice fed WD for 16 weeks. Here we show that the reduction in atherosclerotic lesion size is accompanied by reduced macrophage infiltration and a dramatic reduction in T cell infiltration in lesions of DKO mice (Number of CD3+T cells/mm2; DKO, 275.8±44.9 versus ApoE−/−, 432.1±22.4; P<0.01, n=7/group). DKO mice also have more monocyte progenitors in their bone marrow (number of monocytes/femur; DKO, 9.36×105±1.32×105 versus ApoE−/−, 4.41×105±4.55×104; P<0.01, n=7/group) but fewer circulating monocytes in blood (DKO, 8.30×105±5.16×104 versus ApoE−/−, 1.16×106±1.12×105 monocytes/ml; P<0.01, n=2116/group). Circulating levels of monocyte chemotactic protein-1 (MCP-1) were not different in ApoE−/− and DKO mice fed chow diet (DKO 42.5±7.4 pg/ml versus ApoE−/− 30.1±3.9 pg/ml, n=716/group). Following WD, plasma MCP-1 levels increased in ApoE−/− mice but not in DKO mice (DKO 31.6±4.0 pg/ml versus; ApoE−/− 50.6±9.3 pg/ml n=811/group). As a result plasma MCP-1 was significantly lower in DKO fed WD than in ApoE−/−.
These data indicate that 11β-HSD1 deficiency reduces atherosclerotic lesion formation in ApoE−/− mice by reducing recruitment of inflammatory cells. The mechanisms responsible are currently under investigation.