Endocrine Abstracts

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=21–16/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=7–16/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=8–11/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.