Glucocorticoid response elements and 11 beta-hydroxysteroid dehydrogenases in the regulation of endothelial nitric oxide synthase expression. Cardiovasc Res 2009 Jan 01;81(1):140-7
Date
08/22/2008Pubmed ID
18716005Pubmed Central ID
PMC2639091DOI
10.1093/cvr/cvn231Scopus ID
2-s2.0-57749171127 (requires institutional sign-in at Scopus site) 77 CitationsAbstract
AIMS: Hypertensive and other effects of excess glucocorticoids might be in part mediated by the suppression of endothelial nitric oxide synthase (eNOS) expression. We studied the transcriptional and biochemical mechanisms that mediate or modulate the suppression of eNOS expression by glucocorticoids.
METHODS AND RESULTS: We found that a mere three-fold increase in the concentration of the natural glucocorticoid cortisol (from 30 to 100 nmol/L) significantly decreased the expression level of eNOS in human endothelial cells. Deletion analysis of the eNOS promoter indicated that the segment within -119 bp upstream from the transcription start site was significantly involved in the effect of cortisol. Site-directed mutagenesis and chromatin immunoprecipitation analyses demonstrated the presence of a suppressive glucocorticoid response element (GRE) at -111 to -105 bp. 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) catalyse the interconversion of active and inactive glucocorticoids. The suppression of 11 beta-HSD2 using small interfering RNA markedly exacerbated the inhibition of eNOS by cortisol. The suppression of 11 beta-HSD1 abolished the inhibition of eNOS expression by cortisol.
CONCLUSION: We identified the first GRE in the eNOS promoter region and demonstrated that endogenous 11 beta-HSD1 and 11 beta-HSD2 play significant and distinct roles in modulating the effect of glucocorticoids on eNOS expression.
Author List
Liu Y, Mladinov D, Pietrusz JL, Usa K, Liang MMESH terms used to index this publication - Major topics in bold
11-beta-Hydroxysteroid Dehydrogenase Type 111-beta-Hydroxysteroid Dehydrogenase Type 2
Animals
Base Sequence
Carbenoxolone
Cells, Cultured
Dose-Response Relationship, Drug
Endothelium, Vascular
Enzyme Inhibitors
Glucocorticoids
Humans
Hydrocortisone
Kidney Medulla
Male
Molecular Sequence Data
Nitric Oxide Synthase Type III
Promoter Regions, Genetic
Rats
Rats, Sprague-Dawley
