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)

Elevated total homocysteine (tHcy) levels are associated with increased risk for atherosclerotic cardiovascular disease. tHcy levels are higher in men than in women, and estrogen replacement therapy may reduce tHcy levels in postmenopausal women. The effect of androgenic hormones on tHcy levels in men has not been examined. The present study determined the effect of supraphysiologic doses of testosterone, with or without its aromatization to estradiol, on fasting tHcy levels in 14 normal male weightlifters aged 19-42 years. Subjects received testosterone-enanthate (200 mg/week intramuscularly), the aromatase inhibitor, testolactone (1 g/day orally), or both drugs together in a crossover design. Each treatment lasted 3 weeks and each treatment was separated by a 4-week washout. Both testosterone regimens increased serum testosterone levels, whereas estradiol increased only during testosterone alone. Mean tHcy levels were not significantly altered when testosterone was given alone or together with testolactone. Testolactone did not significantly influence tHcy levels. We conclude that short-term, high-dose testosterone administration does not affect fasting tHcy levels in normal men.
Atherosclerosis 1997 Apr
PMID:The effect of supraphysiologic doses of testosterone on fasting total homocysteine levels in normal men. 912 65

Recent developments have advanced our knowledge of the role of estrogen in the male. Studies of the mutations in CYP19, the gene encoding aromatase, in six females and two males and a mutant estrogen receptor alpha in a man are described. These observations provide illuminating new insights into the critical role of estrogen in the male (as well as female) in the pubertal growth spurt and skeletal maturation, and in the importance of estrogen sufficiency in the accrual and maintenance of bone mass. The weight of evidence supports an effect of androgens on the latter processes, but this effect has not been quantitated. There is a discordance in the estrogen-deficient male between skeletal growth and skeletal maturation and the accrual of bone mass and density. Estrogen synthesis by the testis is limited before puberty, and estrogen deficiency does not affect the age of pubertal onset. Estrogen deficiency in men leads to hypergonadotropism, macroorchidism, and increased testosterone levels. Estrogen lack has a significant effect on carbohydrate and lipid metabolism, and estrogen resistance was associated with evidence of premature coronary atherosclerosis in a man. These observations have highlighted the role of extraglandular estrogen synthesis and intracrine and paracrine actions. In the human, in contrast to nonprimate vertebrates, aromatase deficiency and estrogen resistance (alpha) does not seem to affect gender identity or psychosexual development. The clinical repercussions of mutations in CYP19 on the fetal-placental unit have highlighted the major role of placental aromatase in the protection of the female fetus from androgen excess, thus preventing androgen-induced pseudohermaphrodism and virilization of the mother. These features are compared with the virilization that occurs in utero in the female spotted hyena. The novel features of the aromatase deficiency syndrome in the affected female--in the fetus, during childhood, and at puberty--are discussed, including virilization at puberty and development of polycystic ovaries. The severity of the syndrome correlates with the severity of impairment of aromatase formation in expression systems. Finally, the structural consequences of missense mutations in CYP19 are described in accordance with a model of the structure of human aromatase.
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PMID:Estrogen: consequences and implications of human mutations in synthesis and action. 1129 27

Dehydroepiandrosterone (DHEA) is speculated to have an antiatherosclerotic effect, although the mechanism of action remains unclear. The objective of the current study was to determine whether the antiatherosclerotic effect of DHEA is related to its conversion to estrogen and to define the role of nitric oxide (NO) in the antiatherosclerotic effect of DHEA. Forty-eight oophorectomized rabbits were divided into 5 groups and fed the following diets for 10 weeks: group 1, a regular rabbit diet plus 1% cholesterol (a high-cholesterol diet [HCD]); group 2, an HCD plus 0.3% DHEA; group 3, an HCD plus 0.3% DHEA and fadrozole (2.0 mg x kg(-1) x d(-1)), a specific aromatase inhibitor; group 4, an HCD plus 17beta-estradiol (20 microg x kg(-1) x d(-1)); and group 5, a regular diet. Atherosclerotic lesions, lipid deposition in aortic vessels, and basal and stimulated NO release were measured in the aforementioned groups of rabbits. NO release was measured by using an NO-selective electrode as well as by measuring vascular responses and the plasma NO metabolites nitrite and nitrate. The plasma total cholesterol level was increased, but there were no significant differences in lipid profile in the 4 groups of rabbits that were fed the HCD. The area occupied by atherosclerosis in the thoracic aorta was diminished by approximately 60% in the DHEA-treated rabbits (group 2) compared with the HCD group of rabbits (group 1); there was a corresponding 80% decrease in the estradiol group (group 4) but only a 30% decrease in the DHEA plus fadrozole group (group 3). In the aortas of rabbits from groups 1 and 3, the acetylcholine-induced and tone-related basal NO-mediated relaxations were diminished compared with those of the controls (group 5). However, these relaxations were restored in the aortas of group 2 and 4 rabbits, and an increase in NO release was observed in groups 2 and 4 compared with groups 1 and 3, as measured by an NO-selective electrode. Injection of neither solvent (20% ethanol/distilled water) nor fadrozole significantly affected the atherosclerotic area or the NO-related responses described above. We conclude that approximately 50% of the total antiatherosclerotic effect of DHEA was achieved through the conversion of DHEA to estrogen. NO may also play a role in the antiatherosclerotic effect of DHEA and 17beta-estradiol.
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PMID:Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: the possible role of nitric oxide. 1071 4

It is well documented that estrogens have atheroprotective effects in humans. Peripheral aromatization of circulating androgens has been demonstrated to exert estrogenic actions in many human tissues, especially in men and post-menopausal women. Recently, production of estrogens mediated by aromatase was detected in cultured smooth muscle cells and aortic endothelial cells and it has been proposed that this in situ produced estrogen may influence the development of atherosclerosis. In this study, we first examined aromatase expression by immunohistochemistry in human aortic tissues obtained from 85 autopsy cases (50 males, 35 females, 49.6 +/- 2.9-year-old) and by mRNA in situ hybridization in 10 cases. We then semi-quantified the level of aromatase mRNA in aortic tissues of 12 men and 12 post-menopausal women by reverse transcriptase-polymerase chain reaction (RT-PCR) to examine whether or not and in which cell types aromatase was expressed. We also studied alternative use of multiple exon 1 of its gene and immunolocalization of 17beta-hydroxysteroid dehydrogenase type I (17beta-HSD I), which converts estrone produced by aromatase to estradiol, a biologically active estrogen. Aromatase immunoreactivity and mRNA hybridization signals and 17beta-HSD I immunoreactivity were all detected in smooth muscle cell (SMC) of the media and thickened intima, especially in SMC adjacent to an atheromatous plaque. The levels of aromatase mRNA were significantly higher in female cases than in male cases (P<0.05). The amount of aromatase mRNA was significantly higher in the specimens with fibroatheroma (P<0.05) than other lesions, and was also significantly higher in the cases utilizing 1c (I.3) or 1d (PII) of exon 1, i.e. gonadal types than those utilizing 1b (I.4), i.e. fibroblasts type as the promoter (P<0.01). These results suggest that estrone and estradiol are produced in SMC of the human aortic wall and that their production is mediated by aromatase and 17beta-HSD I, respectively. Moreover, it was suggested that aromatase overexpression, possibly as a result of alternative splicing, may play some roles in the development of atherosclerosis.
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PMID:Aromatase in atherosclerotic lesions of human aorta. 1185 Feb 9

The cytochrome P450 aromatase is the terminal enzyme responsible for the irreversible transformation of androgens into estrogens; it is present in the endoplasmic reticulum membrane of cells and rather ubiquitous in its localization. The aromatase gene is unique in humans and its expression is regulated in a cell-specific manner via the alternative use of various promoters located in the first exon I of the CYP19 gene. The aromatase gene expression and its translation into a fully active protein have been shown in most of the testicular cells including germ cells as well as in the epithelial cells of the epididymis in mammals. Together with the widespread distribution of estrogen receptors (ERalpha and ERbeta) in the genital tract of the male, a physiological role for estrogens in the regulation of mammalian reproductive functions including the regulation of gonadotropin feedback, is now well recognized. Moreover, in men the aromatase deficiency is associated with severe bone maturation problems, alterations of lipid and sugar metabolism and sterility; but conversely an excess of estrogens is responsible for the impairment of spermatogenesis. In addition, estrogens play an important role in the control of osteoporosis and of atherosclerosis, especially in elderly men. Consequently, estradiol seems to be a critical factor not only for normal reproduction (at least for maturation and survival of germ cells) but also for various physiological processes and thus, estrogens should be now considered as "male hormones".
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PMID:Estrogens--male hormones? 1367 29

Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone. They can exert strong effects on the human body that may be beneficial for athletic performance. A review of the literature revealed that most laboratory studies did not investigate the actual doses of AAS currently abused in the field. Therefore, those studies may not reflect the actual (adverse) effects of steroids. The available scientific literature describes that short-term administration of these drugs by athletes can increase strength and bodyweight. Strength gains of about 5-20% of the initial strength and increments of 2-5 kg bodyweight, that may be attributed to an increase of the lean body mass, have been observed. A reduction of fat mass does not seem to occur. Although AAS administration may affect erythropoiesis and blood haemoglobin concentrations, no effect on endurance performance was observed. Little data about the effects of AAS on metabolic responses during exercise training and recovery are available and, therefore, do not allow firm conclusions. The main untoward effects of short- and long-term AAS abuse that male athletes most often self-report are an increase in sexual drive, the occurrence of acne vulgaris, increased body hair and increment of aggressive behaviour. AAS administration will disturb the regular endogenous production of testosterone and gonadotrophins that may persist for months after drug withdrawal. Cardiovascular risk factors may undergo deleterious alterations, including elevation of blood pressure and depression of serum high-density lipoprotein (HDL)-, HDL2- and HDL3-cholesterol levels. In echocardiographic studies in male athletes, AAS did not seem to affect cardiac structure and function, although in animal studies these drugs have been observed to exert hazardous effects on heart structure and function. In studies of athletes, AAS were not found to damage the liver. Psyche and behaviour seem to be strongly affected by AAS. Generally, AAS seem to induce increments of aggression and hostility. Mood disturbances (e.g. depression, [hypo-]mania, psychotic features) are likely to be dose and drug dependent. AAS dependence or withdrawal effects (such as depression) seem to occur only in a small number of AAS users. Dissatisfaction with the body and low self-esteem may lead to the so-called 'reverse anorexia syndrome' that predisposes to the start of AAS use. Many other adverse effects have been associated with AAS misuse, including disturbance of endocrine and immune function, alterations of sebaceous system and skin, changes of haemostatic system and urogenital tract. One has to keep in mind that the scientific data may underestimate the actual untoward effects because of the relatively low doses administered in those studies, since they do not approximate doses used by illicit steroid users. The mechanism of action of AAS may differ between compounds because of variations in the steroid molecule and affinity to androgen receptors. Several pathways of action have been recognised. The enzyme 5-alpha-reductase seems to play an important role by converting AAS into dihydrotestosterone (androstanolone) that acts in the cell nucleus of target organs, such as male accessory glands, skin and prostate. Other mechanisms comprises mediation by the enzyme aromatase that converts AAS in female sex hormones (estradiol and estrone), antagonistic action to estrogens and a competitive antagonism to the glucocorticoid receptors. Furthermore, AAS stimulate erythropoietin synthesis and red cell production as well as bone formation but counteract bone breakdown. The effects on the cardiovascular system are proposed to be mediated by the occurrence of AAS-induced atherosclerosis (due to unfavourable influence on serum lipids and lipoproteins), thrombosis, vasospasm or direct injury to vessel walls, or may be ascribed to a combination of the different mechanisms. AAS-induced increment of muscle tissue can be attributed to hypertrophy and the formation of new muscle fibres, in which key roles are played by satellite cell number and ultrastructure, androgen receptors and myonuclei.
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PMID:Effects of androgenic-anabolic steroids in athletes. 1524 88

Dehydroepiandrosterone sulfate (DHEAS) is a hormone produced by the adrenal gland and is a precursor for both androgens and estrogens. Atherosclerosis is a well characterized inflammatory disease, but little is known about the role of DHEAS in vascular inflammation. We hypothesize that DHEAS can reduce inflammation in vascular endothelial cells and the mechanism involves the peroxisome proliferator-activated receptor alpha (PPARalpha), thereby inhibiting transcription factors involved in endothelial cell inflammation. To test our hypothesis, aortic endothelial cells were pretreated for 48 h with DHEAS, then with TNF-alpha. TNF-alpha-induced upregulation of the expression of inflammatory genes interleukin (IL)-8 and intracellular adhesion molecule (ICAM)-1 was attenuated by incubation with DHEAS. DHEAS inhibited the TNF-alpha-induced surface expression of vascular cell adhesion molecule (VCAM)-1. This effect was abolished by the addition of MK866, a PPARalpha inhibitor, indicating that PPARalpha is involved in the mechanism of this inhibition. The addition of the aromatase inhibitor letrozole had no effect on the inhibition of TNF-alpha-induced VCAM-1 expression by DHEAS. Treatment of endothelial cells with DHEAS dramatically inhibited the TNF-alpha-induced activation of NF-kappaB, an inflammatory transcription factor, and increased protein levels of the NF-kappaB inhibitor, IkappaB-alpha. These results signify the ability of DHEAS to directly inhibit the inflammatory process and show a potential direct effect of DHEAS on vascular inflammation that has implications for the development of atherosclerotic cardiovascular disease.
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PMID:Inhibition of vascular inflammation by dehydroepiandrosterone sulfate in human aortic endothelial cells: roles of PPARalpha and NF-kappaB. 1825 43

Increased oxidative stress and endoplasmic reticulum stress (ER stress) have been implicated in atherosclerosis. Estrogens have potent antioxidant activity but their effects on ER stress have not been well studied. Therefore, we studied the effects of estradiol and related sex steroids on dextrose-induced ER stress and superoxide (SO) generation in human umbilical vein endothelial cells (HUVECs). Oxidative stress was measured using hydroethidine fluorescence and MCLA chemiluminescence. ER stress was measured with an ER stress-sensitive secreted alkaline phosphatase (ES-TRAP) assay and by Western blot analysis of the expression of GRP78, JNK1, and phosphorylated JNK1, markers for ER stress. A supraphysiological dextrose concentration (27.5mM) increased ER stress and SO generation compared to treatment with a physiological concentration (5.5mM) of dextrose. In the presence of estradiol or testosterone (T), ER stress and SO generation were significantly reduced. In contrast to T-treated cells, dihydrotestosterone and 5-methyltestosterone were ineffective at alleviating ER stress or SO generation. When HUVECs were treated with T and the aromatase inhibitor 4-hydroxy-4-androstene-3,17-dione, T was no longer effective at suppressing ER stress or inhibiting SO generation. Changes in GRP78 expression and JNK activity in HUVECs support the results obtained in the ES-TRAP assay. These results indicate that dextrose-induced endoplasmic reticulum stress and superoxide generation are reversed by estradiol and testosterone; however, the latter requires aromatase-dependent conversion to estradiol.
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PMID:Estrogen-dependent inhibition of dextrose-induced endoplasmic reticulum stress and superoxide generation in endothelial cells. 2256 10

The Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors, which plays crucial role in bile acid, cholesterol, lipid and glucose metabolism, as well as in the development of atherosclerosis, intestinal bacterial growth and liver regeneration. FXR is also involved in the pathogenesis of cholestatic diseases, non-alcoholic fatty liver disease and inflammatory bowel disease. Recent evidence further suggests a key role for FXR in apoptosis and cancer. Notably, FXR deficiency promoted intestinal inflammation and tumorigenesis, suggesting that FXR activation might be a promising strategy in the treatment of colon cancer. FXR deficiency in mice led to the development of spontaneous hepatocarcinomas, while FXR inhibition might represent a novel therapeutic approach in Barett's esophagus. In breast cancer cell lines, FXR agonists down-regulated the breast cancer target gene aromatase. FXR inhibited Leydig tumor growth and progression, supporting evidence that FXR may be an important regulator of androgen homoeostasis. Further studies are required in order to establish possible antitumor effects of this nuclear receptor. Either reactivating or inhibiting FXR expression may represent promising therapeutic strategies in the treatment of certain types of human cancer.
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PMID:Farnesoid X Receptor (FXR) from normal to malignant state. 2264 40

Estrogen deficiency is associated with a variety of diseases, including osteoporosis, atherosclerosis, and Alzheimer's disease. Aromatase cytochrome P450 is the only enzyme in vertebrates known to catalyze the biosynthesis of estrogens from androgens. Inhibitors of aromatase have been developed for the treatment of estrogen-dependent breast cancer. However, small molecular agonists of aromatase, which would be useful to locally promote estrogen biosynthesis for the prevention of estrogen deficiency-induced diseases, are rarely reported. In this study, we established a nonradioactive assay for measuring aromatase activity by using human ovarian granulosa KGN cells and identified two estrogen biosynthesis-promoting compounds, egonol gentiobioside and egonol gentiotrioside from Styrax perkinsiae. The compounds also promoted estrogen biosynthesis in 3T3-L1 preadipocyte cells. Further study showed that neither compound affected the transcriptional and translational expression of aromatase in KGN cells, but that both significantly promoted the in vitro enzyme activity of recombinant expressed aromatase. Egonol gentiotrioside was also found to increase the serum estrogen level in ovariectomized rats. These results suggest that these two compounds may promote estrogen biosynthesis through the allosterical regulation of aromatase activity. Egonol gentiobioside and egonol gentiotrioside are, therefore, valuable targets for structural modification and warrant further investigation for their potential as novel pharmaceutical tools for the prevention of estrogen deficiency-induced diseases.
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PMID:Egonol gentiobioside and egonol gentiotrioside from Styrax perkinsiae promote the biosynthesis of estrogen by aromatase. 2279 52


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