Induction of 11β-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli

Cai, Tian-Quan; Wong, Birming; Mundt, Steven S.; Thieringer, Rolf; Wright, Samuel D.; Hermanowski‐Vosatka, Anne

doi:10.1016/s0960-0760(01)00041-3

Cited by 97 publications

(80 citation statements)

References 26 publications

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“…Considering that glucocorticoids have a 10 2 -10 3 -fold blood concentration compared with Aldo, glucocorticoids have to be converted to the deactivated form (cortisone in human, 11-dehydrocorticosterone in rodent) by 11b-hydroxysteroid dehydrogenase type 2 in order to retain the specific action of Aldo by the MR in rVSMCs. Although the expression of 11b-hydroxysteroid dehydrogenase type 2 is limited in the cardiovascular system, 10 Farman 35 reported that the Aldo-MR complex is more stable than the cortisol-MR complex, and the activation of gene transcription by Aldo-MR is about 100-fold higher than that activated by cortisol-MR. Furthermore, Kitagawa 36 suggested that the altered conformation of the A/B region of MR that is induced by Aldo, but not by hydrocortisone, might determine the accessibility of the AF-1a domain of MR to RNA helicase A/CBP complexes.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

et al. 2011

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Osteopontin (OPN) is known to be one of the cytokines that is involved in the vascular inflammation caused by aldosterone (Aldo). Previous reports have shown that Aldo increases OPN transcripts, and the mechanisms for this remain to be clarified. In this study, we investigated how Aldo increases OPN transcripts in the vascular smooth muscle cells of rats. Aldosterone increased OPN transcripts time-dependently as well as dose-dependently. This increase was diminished by eplerenone, a mineralocorticoid receptor (MR) antagonist. Luciferase promoter assays showed that the OPN promoter deleted to the À1599 site retained the same promoting ability as the full-length OPN promoter when stimulated by 10 À7 M Aldo, but the promoter deleted to the À1300 site lost the promoting ability. A glucocorticoid response element (GRE) is located in that deleted region. Luciferase assays of a mutated promoter without the GRE lost the luciferase upregulation, although mutated promoters with the deletion of other consensus sites maintained the promoter activity. The binding of the Aldo-MR complex to the GRE fragment was confirmed by an electrophoretic-mobility shift assay. This is the first report showing that Aldo regulates the transcriptional levels of OPN and inflammatory responses in the vasculature through a specific GRE site in the OPN promoter region.

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Section: Discussionmentioning

confidence: 99%

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

et al. 2011

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“…Additionally, inflammation-induced alterations in 11β-hydroxysteroid dehydrogenase (11βHSD) enzyme activity can alter the equilibrium between the concentration of the active glucocorticoid (i.e., cortisol in humans, corticosterone in rodents) and their inert 11-keto metabolite (i.e., cortisone and 11-dehydrocorticosterone, respectively). Endotoxin and inflammatory cytokines inhibit 11βHSD type 2 and reciprocally increase the activity of 11βHSD type 1 thereby increasing the tissue concentration of the active steroid (51,52). Such an increase in the bioactivity of glucocorticoids within muscle would be expected to impair translational control of protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

Lang

Frost

2006

Mol Med

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Sepsis blunts the ability of nutrient signaling by leucine to stimulate skeletal muscle protein synthesis by impairing translation initiation. The present study tested the hypothesis that overproduction of either tumor necrosis factor (TNF)-α or glucocorticoids mediate the sepsis-induced leucine resistance. Prior to producing peritonitis, rats received either vehicle, TNF binding protein (TNF BP ) to inhibit endogenous TNFα action, and/or the glucocorticoid receptor antagonist RU486. Leucine was orally administered to all rats 24 h thereafter and the gastrocnemius removed 20 min later to assess protein synthesis and signaling components important in controlling peptide-chain initiation. Muscle protein synthesis was 65% lower in septic rats administered leucine than in leucinetreated control animals. This reduction was not prevented by either TNF BP or RU486 alone, but was completely reversed by the combination. This sepsis-induced leucine resistance was associated with an 80% reduction in the amount of active eIF4E·eIF4G complex, a 5-fold increase in the formation of the inactive eIF4E·4E-BP1 complex as well as markedly reduced (at least 70%) phosphorylation of 4E-BP1, eIF4G, S6K1, S6, and mTOR. Pretreatment of septic rats with either TNF BP or RU486 individually only nominally improved the leucine action as assessed by the above-mentioned endpoints. In contrast, when TNF BP and RU486 were co-administered, the ability of sepsis to impair the leucine-stimulated phosphorylation of 4E-BP1, eIF4G, S6K1, and S6 as well as the redistribution of eIF4E was essentially prevented. No differences in the total amount or phosphorylation of eIF2α and eIF2Bε were detected between the different groups, and changes could not be attributed to differences in the prevailing plasma concentration of insulin or leucine. Our data demonstrate the sepsis-induced leucine resistance in skeletal muscle results from the cooperative interaction of both TNFα and glucocorticoids.

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“…More recent studies suggest that 11b-HSD1 influences remodelling responses in the vasculature (see below (63,86)). In vascular cells and macrophages in vitro, pro-inflammatory cytokines up-regulate 11b-HSD1 expression (76,77,87), raising the intriguing possibility that local amplification of cortisol concentrations provides a counter-regulatory response which modifies remodelling during vascular injury or inflammation. However, in in vivo studies we were unable to confirm this phenomenon (88).…”

Section: Glucocorticoid Signalling In Cardiovascular Organsmentioning

confidence: 99%

Glucocorticoids and Cardiovascular Disease

Walker¹

2007

European Journal of Endocrinology

477

386

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Chronic excessive activation of glucocorticoid receptors induces obesity, insulin resistance, glucose intolerance, dyslipidaemia and hypertension. Subtle abnormalities of the hypothalamic-pituitaryadrenal axis and/or of tissue sensitivity to glucocorticoids are also associated with these cardiovascular risk factors in patients with the metabolic syndrome. Furthermore, glucocorticoids have direct effects on the heart and blood vessels, mediated by both glucocorticoid and mineralocorticoid receptors and modified by local metabolism of glucocorticoids by the 11b-hydroxysteroid dehydrogenase enzymes. These effects influence vascular function, atherogenesis and vascular remodelling following intravascular injury or ischaemia. This article reviews the systemic and cardiovascular effects of glucocorticoids, and the evidence that glucocorticoids not only promote the incidence and progression of atherogenesis but also modify the recovery from occlusive vascular events and intravascular injury. The conclusion is that manipulation of glucocorticoid action within metabolic and cardiovascular tissues may provide novel therapeutic avenues to combat cardiovascular disease.European Journal of Endocrinology 157 545-559

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Induction of 11β-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli

Cited by 97 publications

References 26 publications

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element

Glucocorticoids and TNFα Interact Cooperatively to Mediate Sepsis-Induced Leucine Resistance in Skeletal Muscle

Glucocorticoids and Cardiovascular Disease

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