Effects of glucocorticoids and of 11β - hydroxysteroid dehydrogenase type I on vascular smooth muscle cells

Abstract

The actions of glucocorticoids are mediated, in part, by 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which amplifies their effects at the pre-receptor level by converting cortisone to cortisol. Glucocorticoids, such as dexamethasone, inhibit vascular smooth muscle cell proliferation; however, the role of 11β-HSD1 in this response remains unknown. Accordingly, human coronary artery smooth muscle cells (HCSMC) were treated with dexamethasone (10-9 – 10-6 mol/L) and was found that after 72 h, dexamethasone increased 11β-HSD1 expression (14.16 ± 1.6 fold, p<0.001) and activity (6.21 ± 1.2 fold, p<0.001) in a dose- and time-dependent manner, which was dependent upon glucocorticoid receptor (GR) activation and C/EBPβ and C/EBPδ signaling. As glucocorticoids are known to negatively regulate GR expression, the effect of decreasing 11β-HSD1 expression on GR expression was examined. In HCSMC transfected with 11β-HSD1 siRNA, GR expression was increased; this effect was associated with protein kinase A activation and CREB phosphorylation. To examine the role of 11β-HSD1 in HCSMC proliferation, 11β-HSD1 expression was decreased and cells were stimulated with platelet derived growth factor (PDGF) (10 ng/ml). Decreased 11β-HSD1 expression was associated with increased cell proliferation in the absence of PDGF compared to scrambled control-transfected cells (236.10 ± 13.11 %, n=4, p<0.001) and this effect was augmented by PDGF. Furthermore, the inhibitory effect of dexamethasone on cellular proliferation was abrogated in 11β-HSD1 siRNA-transfected HCSMC. Downregulation of 11β-HSD1 was associated with decreased p27kip1 expression and increased phosphorylated retinoblastoma protein, consistent with a proliferative response. These ABSTRACT 7 findings suggest that 11β-HSD1 plays a role in the effects of glucocorticoids on vascular smooth muscle cell phenotype