Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids have been reported to protect against atherosclerosis and have been used clinically as protective therapy for restenosis after balloon angioplasty. Recently, Lp(a) lipoprotein [Lp(a)] levels have been suggested to be an independent risk factor for atherosclerosis, although its mechanisms of action are still uncertain. To clarify this atherogenic mechanism of Lp(a), we investigated the effects of Lp(a) on glucocorticoid receptor (GR) expression in human vascular smooth muscle cells (SMC). Levels of nuclear GR in SMC began to decrease after 12-h incubation with Lp(a), to 55 +/- 8% of the control value at 48 h; binding affinity did not change. Lp(a) had no effect on estrogen receptor binding in SMC. Moreover, low, very low, and high density lipoproteins had no effect on GR binding in SMC. The effects of Lp(a) on nuclear GR in rat SMC were very similar to those in human SMC; in contrast, Lp(a) did not alter GR or estrogen receptor levels in rat endothelial cells. GR messenger RNA levels in SMC decreased after 1-h treatment with Lp(a) to 23% of the control value after 12 h. Further, the antiproliferative effect of glucocorticoids on SMC was blunted by exposure to Lp(a). We conclude that Lp(a) down-regulates GR gene expression, resulting in a decreased number of GR in SMC. These findings suggest the possibility of a novel atherogenic mechanism of Lp(a) via inhibition of a protective action of glucocorticoids on SMC.
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PMID:Glucocorticoid receptor expression is down-regulated by Lp(a) lipoprotein in vascular smooth muscle cells. 764 76

Treatment with glucocorticoids increases the concentration of plasma high-density lipoprotein (HDL), which is inversely correlated to the development of atherosclerosis. Previously, we demonstrated that repeated administration of glucocorticoids increases apolipoprotein (apo) A-I gene expression and decreases apoA-II gene expression in rat liver. In the present study, the mechanism of glucocorticoid action on hepatic apoA-I and apoA-II expression was studied. A single injection of rats with dexamethasone increased hepatic apoA-I mRNA levels within 6 h and further increases were observed after 12 h and 24 h. In contrast, liver apoA-II mRNA levels gradually decreased after dexamethasone treatment to less than 25% control levels after 24 h. In rat primary hepatocytes and McARH8994 hepatoma cells, addition of dexamethasone increased apoA-I mRNA levels in a time-dependent and dose-dependent manner, whereas apoA-II mRNA levels were unchanged. Simultaneous addition of the glucocorticoid antagonist RU486 prevented the increase in apoA-I mRNA levels after dexamethasone treatment, which suggests that the effects of dexamethasone are mediated through the glucocorticoid receptor. Inhibition of transcription by actinomycin D and nuclear-run-on experiments in McARH8994 cells and primary hepatocytes showed that dexamethasone induced apoA-I, but not apoA-II, gene transcription. Transient-transfection assays in McARH8994 cells with a chloramphenicol acetyl transferase vector driven by the rat-apoA-I-gene promoter demonstrated that the proximal apoA-I promoter could be induced by dexamethasone, and this effect could be abolished by simultaneous treatment with RU486. However, in COS-1 cells, apoA-I promoter transcription was not induced by dexamethasone or cotransfected glucocorticoid receptor. In addition, the induction of apoA-I gene transcription by dexamethasone was blocked by the protein-synthesis inhibitor cycloheximide, which suggests the presence of a labile protein involved in apoA-I gene activation by dexamethasone. In conclusion, our results demonstrate that dexamethasone regulates rat apoA-I, but not apoA-II, gene expression through direct action on the hepatocyte. The induction of apoA-I gene transcription by dexamethasone requires the glucocorticoid receptor and a labile cell-specific protein.
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PMID:Transcriptional induction of rat liver apolipoprotein A-I gene expression by glucocorticoids requires the glucocorticoid receptor and a labile cell-specific protein. 870 54

-Recent reports suggest that the increased production of reactive oxygen species (ROS) in the vascular wall may contribute to the functional and structural changes associated with hypertension and atherosclerosis. Although glucocorticoid therapy can promote atherosclerosis, protective effects of these compounds on vascular lesion formation have been reported. In the present study, we investigated whether ROS production in cultured human aortic smooth muscle cells (HSMCs) can be modulated by glucocorticoids. Pretreatment of HSMCs with dexamethasone for 24 hours attenuated the basal and platelet-derived growth factor (PDGF)-AB- and angiotensin II-induced superoxide anion (O2. -) production. PDGF-AB-stimulated O2. - production was also inhibited by prednisolone and hydrocortisone but not by other steroids, such as testosterone and norgestrel. Incubation of HSMCs with glucocorticoids for 24 hours decreased 2',7'-dichlorodihydrofluorescein (DCHF) oxidation, an indicator of intracellular ROS levels. Dexamethasone decreased the mRNA expression of p22 phox, one of the components of NADPH oxidase, but had no effect on the activity of superoxide dismutase. The effects of dexamethasone on DCHF oxidation, and p22 phox mRNA expression and PDGF-AB-stimulated O2. - production were inhibited by the glucocorticoid receptor antagonist RU486. These results indicate that glucocorticoids decrease O2. - production by HSMCs via a receptor-dependent pathway. This effect is likely to be mediated by a decrease in the generating system, such as downregulation of p22 phox mRNA, rather than an increased inactivation of O2. -. The inhibition of ROS production might contribute to the local protective effects that glucocorticoids have on vascular lesion formation.
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PMID:Glucocorticoids inhibit superoxide anion production and p22 phox mRNA expression in human aortic smooth muscle cells. 985 78

Mechanisms that control the balance between cell proliferation and death are important in the development of vascular lesions. Rat primary smooth muscle cells were 80% inhibited by low microgram doses of hydrocortisone (HC) and 50% inhibited by nanogram concentrations of transforming growth factor-beta1 (TGF-beta1), although some lines acquired resistance in late passage. However, comparable doses of HC, or TGF-beta1, failed to inhibit most human lesion-derived cell (LDC) lines. In sensitive LDC, HC (10 microg/mL) inhibited proliferation by up to 50%, with obvious apoptosis in some lines, and TGF-beta1 inhibited proliferation by more than 90%. Collagen production, as measured by [3H]proline incorporation or RIA for type III pro-collagen, was either unaffected or increased in the LDCs by HC. These divergent responses between LDC lines were partially explained by the absence of the glucocorticoid receptor (GR) and heat shock protein 90 mRNA in 10 of 12 LDC lines, but the presence of the mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type II. Western blot analysis confirmed the absence of the GR protein in cells lacking GR mRNA. Immunohistochemistry of human carotid lesions showed high levels of GR in the tunica media, but large areas lacking GR in the fibrous lesion. Considering the absence of the GR in most lines, the effects of HC may be elicited through the mineralocorticoid receptor. Functional resistance to the antiproliferative and antifibrotic effects of HC may contribute to excessive wound repair in atherosclerosis and restenosis.
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PMID:Glucocorticoid resistance caused by reduced expression of the glucocorticoid receptor in cells from human vascular lesions. 1032 68

Glucocorticoid, an anti-inflammatory agent, inhibits the development of atherosclerosis in various experimental animal models. This is partially explained by its ability to inhibit smooth muscle cell migration and proliferation in the intima and to reduce chemotaxis of circulating monocytes and leukocytes into the subendothelial spaces. We have recently demonstrated that oxidized LDL (Ox-LDL) has a mitogenic activity for macrophages in vitro in which Ox-LDL-induced granulocyte/macrophage colony-stimulating factor (GM-CSF) production plays an important role. Proliferation of cellular components is one of the characteristic events in the development and progression of atherosclerotic lesions. In the present study, we investigated the effects of glucocorticoids on Ox-LDL-induced macrophage growth. Dexamethasone, prednisolone, and cortisol inhibited Ox-LDL-induced thymidine incorporation into macrophages by 85%, 70%, and 50%, respectively. Ox-LDL induced a significant production of GM-CSF by macrophages, which was effectively inhibited by dexamethasone, prednisolone, and cortisol by 80%, 65%, and 50%, respectively. Dexamethasone-mediated inhibition of Ox-LDL-induced GM-CSF mRNA expression and macrophage growth was significantly abrogated by RU-486, a glucocorticoid receptor antagonist. Our results suggest that the inhibitory effects of glucocorticoids on macrophage growth may be due to the inhibition of Ox-LDL-induced GM-CSF production through transactivation of the glucocorticoid receptor.
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PMID:Glucocorticoid inhibits oxidized LDL-induced macrophage growth by suppressing the expression of granulocyte/macrophage colony-stimulating factor. 1039 91

The effect of the glucocorticoid receptor (GRL) gene Bcl I polymorphism on body composition and metabolic changes in response to overfeeding was studied. Twenty-four men (mean age 21+/-2 years) who constituted 12 pairs of identical twins ate a 4.2 MJ/day energy surplus, 6 days a week, during a period of 100 days. The GRL Bcl I marker was identified by Southern Blot technique. Total body fat was assessed by hydrodensitometry and abdominal fat areas were measured by computed tomography. Fasting plasma glucose and insulin during an oral glucose tolerance test (OGTT) were assayed. The insulin and glucose areas were computed using the trapezoidal method. Triglyceride and cholesterol concentrations in plasma and lipoprotein fractions were determined enzymatically. The results showed that overfeeding induced a greater increase in body weight (p=0.002) in the 2.3/2.3 kb (n=12) than in the 4.5/2.3 kb (n=12) subjects. In addition, plasma levels of total (p=0.007) and low-density lipoprotein (LDL) cholesterol (p=0.003), as well as systolic blood pressure (p=0.036) increased more in the 2.3/2.3 kb than in the 4.5/2.3 kb subjects. The 2.3/2.3 kb genotype was also associated with a greater increase in abdominal visceral fat (p=0.040) compared to the 4.5/2.3 kb genotype. In conclusion, 2.3/2.3 kb subjects of the GRL Bcl I polymorphism experience greater increases in body weight, blood pressure and cholesterol levels as well as visceral fat than 4.5/2.3 kb subjects in response to overfeeding. These data suggest that overfeeding induces an atherogenic profile in subjects who are homozygotes for the 2.3 kb allele.
Atherosclerosis 2001 Jul
PMID:Glucocorticoid receptor Bcl I variant is associated with an increased atherogenic profile in response to long-term overfeeding. 1142 24

Macrophages play diverse roles in host defense and in maintenance of homeostasis. Based on their ability to promote inflammatory responses, inappropriate macrophage function also contributes to numerous pathological processes, including atherosclerosis, rheumatoid arthritis and inflammatory bowel disease. Members of the nuclear receptor superfamily of ligand-dependent transcriptions factors have emerged as key regulators of inflammation and lipid homeostasis in macrophages. These include the glucocorticoid receptor (GR), which inhibits inflammatory programs of gene expression in response to natural corticosteroids and synthetic anti-inflammatory ligands such as dexamethasone. Also, in response to endogenous eicosanoids and oxysterols, respectively, peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) regulate transcriptional programs involved in inflammatory responses and lipid homeostasis. Identification of their mechanisms of action should help guide the development of new therapeutic agents useful in the treatment of diseases in which macrophages play critical pathogenic roles.
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PMID:Nuclear receptor signaling in macrophages. 1469 33

The role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in the local activation of the glucocorticoid receptor by converting inactive 11-ketoglucocorticoids to active 11beta-hydroxyglucocorticoids is well established. Currently, 11beta-HSD1 is considered a promising target for treatment of obese and diabetic patients. Here, we demonstrate a role of 11beta-HSD1 in the metabolism of 7-ketocholesterol (7KC), the major dietary oxysterol. Comparison of recombinant 11beta-HSD1, transiently expressed in human embryonic kidney 293 cells, revealed the stereo-specific interconversion of 7KC and 7beta-hydroxycholesterol by rat and human 11beta-HSD1, whereas the hamster enzyme interconverted 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7KC. In contrast to lysates, which efficiently catalyzed both oxidation and reduction, intact cells exclusively reduced 7KC. These findings were confirmed using rat and hamster liver homogenates, intact rat hepatocytes, and intact hamster liver tissue slices. Reduction of 7KC was abolished upon inhibition of 11beta-HSD1 by carbenoxolone (CBX) or 2'-hydroxyflavanone. In vivo, after gavage feeding rats, 7KC rapidly appeared in the liver and was converted to 7beta-hydroxycholesterol. CBX significantly decreased the ratio of 7beta-hydroxycholesterol to 7KC, supporting the evidence from cell culture experiments for 11beta-HSD1-dependent reduction of 7KC to 7beta-hydroxycholesterol. Upon inhibition of 11beta-HSD1 by CBX, 7KC tended to accumulate in the liver, and plasma 7KC concentration increased. Together, our results suggest that 11beta-HSD1 efficiently catalyzes the first step in the rapid hepatic metabolism of dietary 7KC, which may explain why dietary 7KC has little or no effect on the development of atherosclerosis.
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PMID:Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, and hamster enzyme. 1497 25

Fatty acid metabolism is abnormal in insulin-resistant states that increase the risk of atherosclerosis such as type 2 diabetes and the metabolic syndrome. How fatty acids promote vascular disease is poorly understood, but lipoprotein lipase and peroxisome proliferator-activated receptor alpha (PPARalpha)-physiologically related proteins involved in fatty acid metabolism-may be involved. Glucocorticoid metabolism is also abnormal in insulin-resistant states and may promote several components of the metabolic syndrome. Recent studies have shown that hepatic fatty acid metabolism is required for the development of insulin resistance and hypertension caused by glucocorticoid excess, suggesting that crosstalk between glucocorticoid receptor-and PPARalpha-dependent pathways may contribute to vascular disease.
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PMID:Fatty acid metabolism and vascular disease. 1503 Jul 93

Interconversion between cortisone and the glucocorticoid receptor ligand cortisol is carried out by 11beta-hydroxysteroid dehydrogenase (11beta-HSD)isozymes and constitutes a medically important example of pre-receptor control of steroid hormones. The enzyme 11beta-HSD type 1 (11beta-HSD1) catalyzes the conversion of cortisone to its active receptor-binding derivative cortisol, whereas 11beta-HSD type 2 performs the reverse reaction. Specific inhibitors against the type 1 enzyme lower intracellular levels of glucocorticoid hormone, with an important clinical application in insulin resistance and other metabolic disorders. We report here on the in vitro oxysterol-metabolizing properties of human and rodent 11beta-HSD1. The enzyme, either as full-length, membrane-attached, or as a transmembrane domain-deleted, soluble form, mediates exclusively conversion between 7-ketocholesterol and 7beta-hydroxycholesterol with similar k(cat) values as observed with glucocorticoid hormones. Thus, human, rat, and mouse 11beta-HSD1 have dual enzyme activities like the recently described 7alpha-hydroxysteroid dehydrogenase/11beta-hydroxysteroid dehydrogenase from hamster liver, but differ fundamentally from the latter in that 7beta-OH rather than 7alpha-OH dehydrogenase constitutes the second activity. These results demonstrate an enzymatic origin of species differences in 7-oxysterol metabolism, establish the origin of endogenous 7beta-OH cholesterol in humans, and point to a possible involvement of 11beta-HSD1 in atherosclerosis.
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PMID:Human and rodent type 1 11beta-hydroxysteroid dehydrogenases are 7beta-hydroxycholesterol dehydrogenases involved in oxysterol metabolism. 1509 19


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