Glucocorticoid response elements and 11β-hydroxysteroid dehydrogenases in the regulation of endothelial nitric oxide synthase expression

被引:72
作者
Liu, Yong [1 ]
Mladinov, Domagoj [1 ]
Pietrusz, Jennifer L. [1 ]
Usa, Kristie [1 ]
Liang, Mingyu [1 ]
机构
[1] Med Coll Wisconsin, Dept Physiol, Milwaukee, WI 53226 USA
基金
美国国家卫生研究院;
关键词
HUMAN ESSENTIAL-HYPERTENSION; SALT-SENSITIVE HYPERTENSION; OXIDATIVE STRESS; GENE-EXPRESSION; TYPE-2; RECEPTOR; CELLS; MECHANISMS; RATS; LOCALIZATION;
D O I
10.1093/cvr/cvn231
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. 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. 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.
引用
收藏
页码:140 / 147
页数:8
相关论文
共 41 条
[31]   11β-hydroxysteroid dehydrogenase antisense affects vascular contractile response and glucocorticoid metabolism [J].
Souness, GW ;
Brem, AS ;
Morris, DJ .
STEROIDS, 2002, 67 (3-4) :195-201
[32]  
STEWART PM, 1987, LANCET, V2, P821
[33]   NADPH oxidase in the renal medulla causes oxidative stress and contributes to salt-sensitive hypertension in Dahl S rats [J].
Taylor, NE ;
Glocka, P ;
Liang, MY ;
Cowley, AW .
HYPERTENSION, 2006, 47 (04) :692-698
[34]   Renal regional proteomes in young Dahl salt-sensitive rats [J].
Tian, Zhongmin ;
Greene, Andrew S. ;
Usa, Kristie ;
Matus, Isaac R. ;
Bauwens, Jesse ;
Pietrusz, Jennifer L. ;
Cowley, Allen W., Jr. ;
Liang, Mingyu .
HYPERTENSION, 2008, 51 (04) :899-904
[35]   MicroRNA-target pairs in the rat kidney identified by microRNA microarray, proteomic, and bioinformatic analysis [J].
Tian, Zhongmin ;
Greene, Andrew S. ;
Pietrusz, Jennifer L. ;
Matus, Isaac R. ;
Liang, Mingyu .
GENOME RESEARCH, 2008, 18 (03) :404-411
[36]   11β-hydroxysteroid dehydrogenase type 1:: A tissue-specific regulator of glucocorticoid response [J].
Tomlinson, JW ;
Walker, EA ;
Bujalska, IJ ;
Draper, N ;
Lavery, GG ;
Cooper, MS ;
Hewison, M ;
Stewart, PM .
ENDOCRINE REVIEWS, 2004, 25 (05) :831-866
[37]  
Usa K, 2007, AM J PHYSIOL-RENAL, V293, pF186, DOI 10.1152/ajprenal.00484.2006
[38]   Down-regulation of the expression of endothelial NO synthase is likely to contribute to glucocorticoid-mediated hypertension [J].
Wallerath, T ;
Witte, K ;
Schäfer, SC ;
Schwarz, PM ;
Prellwitz, W ;
Wohlfart, P ;
Kleinert, H ;
Lehr, HA ;
Lemmer, B ;
Förstermann, U .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (23) :13357-13362
[39]   Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks [J].
Watson, B ;
Bergman, SM ;
Myracle, A ;
Callen, DF ;
Acton, RT ;
Warnock, DG .
HYPERTENSION, 1996, 28 (03) :478-482
[40]   Possible association but no linkage of the HSD11B2 gene encoding the kidney isozyme of 11β-hydroxysteroid dehydrogenase to hypertension in Black people [J].
White, PC ;
Agarwal, AK ;
Li, AR ;
Nikkila, H ;
Pratt, JH ;
Caulfield, M ;
Clark, A ;
McTernan, C ;
Stewart, PM .
CLINICAL ENDOCRINOLOGY, 2001, 55 (02) :249-252