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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enhanced vascular responsiveness to angiotensin II at the AT1 receptor has been considered one of the major contributing factors to vascular hypertrophy and high blood pressure. The transcription of the rat angiotensin II type 1A receptor gene is stimulated by glucocorticoids. To clarify the molecular mechanism for glucocorticoid action in rat vascular smooth muscle cells, we investigated the effects of dexamethasone on the promoter activity of the angiotensin II type 1A receptor by using promoter/luciferase reporter gene constructs and heterologous context constructs (containing the thymidine kinase promoter) in transfected vascular smooth muscle cells (< 12 passages). There are three putative glucocorticoid responsive elements (GREs) in the promoter. However, only one GRE was found to respond to dexamethasone (1 mumol/L) and was located at positions -756 to -770 bp upstream from the transcription initiation site. When compared with the consensus sequence of GRE, 9 of 12 bases were identical. RU38486, a glucocorticoid antagonist, completely blocked the induction by dexamethasone, suggesting that the GRE was functional through a specific glucocorticoid receptor. The response to dexamethasone was lost in vascular smooth muscle cells at higher passage numbers (> 8 passages) but was restored when the cells were transfected with a glucocorticoid-receptor expression construct. This finding provided additional support that the response to dexamethasone was mediated by the glucocorticoid receptor. The gel mobility supershift assay showed that the GRE binds in vitro-translated rat glucocorticoid receptors in a specific manner. Compared with the angiotensin II type 1A receptor promoter, no effect by dexamethasone was observed in vascular smooth muscle cells transfected with the angiotensin II type 1B receptor promoter/luciferase reporter gene constructs.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Identification of a cis-acting glucocorticoid responsive element in the rat angiotensin II type 1A promoter. 761 11

The effects of different steroids on the expression of angiotensin AT1 receptors by the human hepatoma cell line, PLC-PRF-5 was studied. Dexamethasone and aldosterone decreased the specific binding of [3H]angiotensin II to intact PLC-PRF-5 cells by 57 +/- 4% and 54 +/- 2%, respectively, compared to control, untreated cells. EC50 values for dexamethasone, cortisol and aldosterone were 1.8 +/- 0.6, 40 +/- 6, and 310 +/- 20 nM, respectively, suggesting that these effects were mediated via a glucocorticoid receptor. Scatchard analysis revealed that dexamethasone decreased the number of angiotensin AT1 receptors expressed (50 +/- 4% relative to control) with no change in receptor affinity. Treating cells with dexamethasone in the presence of either an angiotensin converting enzyme inhibitor or an angiotensin II receptor antagonist did not prevent the reduction in angiotensin AT1 receptor expression, ruling out a mechanism involving a dexamethasone induced increase in endogenous angiotensin II production. A ribonuclease protection assay established that the steady state level of angiotensin AT1 receptor mRNA in dexamethasone treated cells was reduced to 34.7 +/- 8.4% of untreated cells. The decrease in the number of angiotensin AT1 receptors expressed on the cell surface after treatment with dexamethasone therefore seems likely to reflect the decreased steady state level of the mRNA coding for this receptor.
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PMID:Glucocorticoids regulate the expression of angiotensin AT1 receptors, in the human hepatoma cell line, PLC-PRF-5. 777 81

Vascular tone is maintained by both angiotensin II (Ang II) and glucocorticoids, but the effect of glucocorticoids on Ang II function in vascular smooth muscle cells (VSMC) is unclear. To determine the direct influence of glucocorticoids on VSMC Ang II receptor function, the effects of dexamethasone on Ang II receptor binding, Ang II-induced phospholipase C (PLC) activation, and Ang II-dependent cell growth were studied in cultured rat VSMC. Dexamethasone caused concentration- and time-dependent increases in Ang II binding which were prevented by glucocorticoid receptor inhibition with RU 38486. Dexamethasone-induced enhancement of Ang II binding resulted from increased AT1 receptors, as indicated by Northern blot analysis and competitive binding assays. Despite causing increased Ang II receptor number, dexamethasone preincubation prevented Ang II-induced PLC activation, as indicated by phosphatidylinositol 4,5-bisphosphate degradation and inositol trisphosphate formation. When PLC activity was directly measured in VSMC soluble and membrane fractions, Ang II receptor activation caused decreased soluble and increased membrane PLC activity, consistent with the interpretation that Ang II caused cytosol-to-membrane PLC translocation. The effect of Ang II on PLC translocation was prevented by dexamethasone preincubation. Finally, prolonged incubation with dexamethasone and Ang II had additive effects on VSMC hypertrophy. In conclusion, glucocorticoids directly altered Ang II function in VSMC by causing increased Ang II receptor number, Ang II receptor/PLC uncoupling, and enhanced Ang II-dependent hypertrophy.
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PMID:Glucocorticoid uncoupling of antiogensin II-dependent phospholipase C activation in rat vascular smooth muscle cells. 799 88

We have investigated the effects of maternal nutrient restriction in the sheep during the period of rapid placental growth (i.e. 28-77 days gestation; term = 147 days) on feto-placental growth and expression of the glucocorticoid receptor (GR), types 1 and 2 11beta-hydroxysteroid dehydrogenase (11betaHSD1, 11betaHSD2), and types 1 and 2 angiotensin II receptor (AT1, AT2) in fetal and neonatal offspring. Ewes (n = 63) of similar age, body weight, and body composition were randomly allocated to a nutrient-restricted (NR) group in which they consumed 3.2 MJ/day metabolizable energy (ME; equivalent to 50% of predicted requirements) or to a control group in which they consumed 6.7 MJ/day ME (equivalent to 110% of predicted requirements). After 77 days gestation, ewes from both dietary groups consumed close to 100% of ME requirements up to term. Newborn offspring of NR ewes were of similar body weight, but had increased crown-rump length, greater placental weight, and increased placental/body weight ratio (P < 0.01) compared with controls. Their kidneys were heavier (P < 0.05), but shorter in length, with increased ratios of transverse width to length (P < 0.001). GR messenger RNA (mRNA) expression in neonatal offspring from NR ewes was increased in adrenal, kidney, liver, lung, and perirenal adipose tissue (P < 0.01). Conversely, 11betaHSD1 mRNA expression was unaffected, except in perirenal adipose tissue, where it was higher in lambs born to NR ewes (P < 0.01). 11betaHSD2 mRNA expression was decreased in adrenals and kidney (P < 0.001). Maternal NR also resulted in significantly increased AT1 expression in those tissues in which expression of GR was increased and/or 11betaHSD2 was decreased, i.e. adrenals, kidney, liver, and lung. AT2 expression was unaffected by maternal NR. Although 11betaHSD2 mRNA was undetectable in term placenta, it was abundant in midgestation placenta and was lower after maternal NR (P < 0.001). There was close agreement between levels of 11betaHSD enzyme (i.e. 11beta-dehydrogenase and 11-oxoreductase) activities and abundance of 11betaHSD1 mRNA and 11betaHSD2 mRNA expression. The persistence of tissue-specific increases in the expression of GR, 11betaHSD1 and AT1 and decreases in the expression of 11betaHSD2 in adrenals and kidney in newborn offspring in response to a defined period of maternal nutrient restriction during early to midgestation suggests that gene expression has been programmed by nutrient availability to the fetus before birth. These data suggest key potential mechanisms by which maternal nutrition prenatally programs physiological pathways, such as the renin-angiotensin system, in the offspring that may lead to raised blood pressure and other cardiovascular disease risk factors in later life.
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PMID:Maternal undernutrition during early to midgestation programs tissue-specific alterations in the expression of the glucocorticoid receptor, 11beta-hydroxysteroid dehydrogenase isoforms, and type 1 angiotensin ii receptor in neonatal sheep. 1141 4

Protein phosphatase 5 (PP5) is a unique member of the PPP family of serine/threonine phosphatases based on the presence of tetratricopeptide repeat (TPR) domains within its structure. Since its discovery, PP5 has been implicated in wide ranging cellular processes, including MAPK-mediated growth and differentiation, cell cycle arrest and DNA damage repair via the p53 and ATM/ATR pathways, regulation of ion channels via the membrane receptor for atrial natriuretic peptide, the cellular heat shock response as mediated by heat shock transcription factor, and steroid receptor signaling, especially glucocorticoid receptor (GR). Given this diversity of effects, the recent development of viable PP5-deficient mice was surprising and suggests that PP5 is a modulatory, rather than essential, factor in phosphorylation pathways. Here, we review the signaling involvement of PP5 in light of new findings and relate these activities to the structural features of the protein.
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PMID:Protein phosphatase 5. 1795 Oct 98

Angiotensin II acts through two pharmacologically distinct receptors known as AT1 and AT2. Duplication of the AT1 receptor in rodents into At1a and b subtypes allows tissue-specific expression of the AT1b in adrenal and pituitary tissue. Adrenal expression of this receptor is increased in the offspring of rat mothers exposed to a low-protein diet and this is associated with the undermethylation of its promoter. This phenomenon is blocked by the inhibition of maternal glucocorticoid synthesis by metyrapone. We have mapped the transcriptional start site of the promoter and demonstrated that a 1.2 kbp fragment upsteam of this site is effective in driving luciferase expression in mouse Y1 cells. A combination of bioinformatic analysis, electrophoretic mobility shift analysis (EMSA), and mutagenesis studies demonstrates: i) the presence of a putative TATA box and CAAT box; ii) the presence of three Sp1 response elements, capable of binding SP1; mutation of any pair of these sites effectively disables this promoter; iii) the presence of four potential glucocorticoid response elements which each bind glucocorticoid receptor in EMSA, although only two confer dexamethasone inhibition on the promoter; iv) the presence of two AP1 sites. Mutagenesis of the distal AP1 site greatly diminishes promoter function but this is also associated with the loss of dexamethasone inhibition. These studies will facilitate an understanding of the mechanisms by which fetal programming leads to long term alterations in gene expression and the development of adult disease.
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PMID:Characterization of the angiotensin (AT1b) receptor promoter and its regulation by glucocorticoids. 1941 5

The increase in myocardial reactive oxygen species after epidermal growth factor receptor transactivation is a crucial step in the autocrine/paracrine angiotensin II/endothelin receptor activation leading to the slow force response to stretch (SFR). Since experimental evidence suggests a link between angiotensin II or its AT1 receptor and the mineralocorticoid receptor (MR), and MR transactivates the epidermal growth factor receptor, we thought to determine whether MR activation participates in the SFR development in rat myocardium. We show here that MR activation is necessary to promote reactive oxygen species formation by a physiological concentration of angiotensin II (1 nmol l(-1)), since an increase in superoxide anion formation of ~50% of basal was suppressed by blocking MR with spironolactone or eplerenone. This effect was also suppressed by blocking AT1, endothelin (type A) or epidermal growth factor receptors, by inhibiting NADPH oxydase or by targeting mitochondria, and was unaffected by glucocorticoid receptor inhibition. All interventions except AT1 receptor blockade blunted the increase in superoxide anion promoted by an equipotent dose of endothelin-1 (1 nmol l(-1)) confirming that endothelin receptors activation is downstream of AT1. Similarly, an increase in superoxide anion promoted by an equipotent dose of aldosterone (10 nmol l(-1)) was blocked by spironolactone or eplerenone, by preventing epidermal growth factor receptor transactivation, but not by inhibiting glucocorticoid receptors or protein synthesis, suggesting non-genomic MR effects. Combination of aldosterone plus endothelin-1 did not increase superoxide anion formation more than each agonist separately. We found that aldosterone increased phosphorylation of the redox-sensitive kinases ERK1/2-p90RSK and the NHE-1, effects that were eliminated by eplerenone or by preventing epidermal growth factor receptor transactivation. Finally, we provide evidence that the SFR is suppressed by MR blockade, by preventing epidermal growth factor receptor transactivation or by scavenging reactive oxygen species, but it is unaffected by glucocorticoid receptor blockade or protein synthesis inhibition. Our results suggest that MR activation is a necessary step in the stretch-triggered reactive oxygen species-mediated activation of redox-sensitive kinases upstream NHE-1.
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PMID:Mineralocorticoid receptor activation is crucial in the signalling pathway leading to the Anrep effect. 2217 46