Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11beta-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.
Hypertension 2007 Jan
PMID:Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency. 1707 29

A number of naturally occurring polymorphisms exist in the human angiotensinogen locus, some of which have been associated with essential hypertension, preeclampsia, and other medical disorders. However, to date there has been no comprehensive determination of the significance of specific haplotypes in relation to the regulation of angiotensinogen expression. We cloned the promoters extending from -1219 to +125 bp from 11 ethnically diverse individuals to acquire a representative cross-section of known haplotype diversity. Eight nonredundant haplotypes were identified, fused to luciferase, and studied for their effect on transcriptional regulation in human astrocyte, proximal tubule, and hepatocyte cell lines endogenously expressing angiotensinogen and in a mouse adipocyte cell line. The studies were carried out under baseline conditions, in the presence of the angiotensinogen enhancer, and in response to hormonal stimulation by dexamethasone, beta-estradiol, or testosterone. A statistical model was then constructed to assess the significance of individual polymorphisms. The polymorphisms with the greatest effect on transcription in these cell lines were located at -20 and -217. There were modest haplotype-specific effects of the angiotensinogen enhancer and no haplotype-specific effects of beta-estradiol, dexamethasone, or testosterone treatment. We conclude the following: (1) the -20 and -217 polymorphisms have the largest influence on angiotensinogen transcription, (2) other polymorphisms have a much smaller impact on angiotensinogen transcription, and (3) the transcriptional influence of the promoter polymorphisms may act cell specifically. Therefore, our data support a hypothesis that polymorphisms in the angiotensinogen promoter may act cell specifically to differentially regulate the level of angiotensinogen transcription in angiotensin-producing tissues.
Hypertension 2007 Mar
PMID:The -20 and -217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells. 1720 Apr 39

The majority of familial pulmonary arterial hypertension (PAH) cases are caused by mutations in the type 2 bone morphogenetic protein receptor (BMPR2). However, less than one-half of BMPR2 mutation carriers develop PAH, suggesting that the most important function of BMPR2 mutation is to cause susceptibility to a "second hit." There is substantial evidence from the literature implicating dysregulated inflammation, in particular the cytokine IL-6, in the development of PAH. We thus hypothesized that the BMP pathway regulates IL-6 in pulmonary tissues and conversely that IL-6 regulates the BMP pathway. We tested this in vivo using transgenic mice expressing an inducible dominant negative BMPR2 in smooth muscle, using mice injected with an IL-6-expressing virus, and in vitro using small interfering RNA (siRNA) to BMPR2 in human pulmonary artery smooth muscle cells (PA SMC). Consistent with our hypothesis, we found upregulation of IL-6 in both the transgenic mice and in cultured PA SMC with siRNA to BMPR2; this could be abolished with p38(MAPK) inhibitors. We also found that IL-6 in vivo caused a twofold increase in expression of the BMP signaling target Id1 and caused increased BMP activity in a luciferase-reporter assay in PA SMC. Thus we have shown both in vitro and in vivo a complete negative feedback loop between IL-6 and BMP, suggesting that an important consequence of BMPR2 mutations may be poor regulation of cytokines and thus vulnerability to an inflammatory second hit.
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PMID:Interaction of interleukin-6 and the BMP pathway in pulmonary smooth muscle. 1732 83

Mutations in genes encoding members of the transforming growth factor (TGF)-beta superfamily have been identified in idiopathic forms of pulmonary arterial hypertension (PAH). The current study examined whether perturbations to the TGF-beta/Smad2,3 signalling axis occurred in a monocrotaline (MCT) rodent model of experimental PAH. Expression of the TGF-beta signalling machinery was assessed in the lungs and kidneys of MCT-treated rodents with severe PAH by semi-quantitative reverse-transcription (RT)-PCR, real-time RT-PCR and immunoblotting. TGF-beta signalling was assessed in the lungs and in pulmonary artery smooth muscle cells (PASMC) from MCT-treated rodents by Smad2 phosphorylation, expression of the connective tissue growth factor gene, activation of the serpine promoter in a luciferase reporter system and by the induction of apoptosis. The expression of type1 TGF-beta receptor (TGFBR) activin-A receptor-like kinase1, TGFBR-2, TGFBR-3 (endoglin), Smad3 and Smad4; as well as TGF-beta signalling and TGF-beta-induced apoptosis, were dramatically reduced in the lungs and PASMC, but not the kidneys, of MCT-treated rodents that developed severe PAH. The current data indicate that the transforming growth factor-beta/Smad2,3 signalling axis is functionally impaired in monocrotaline-treated rodents with severe pulmonary arterial hypertension, underscoring the potential importance of transforming growth factor-beta/Smad2,3 signalling in the onset or development of pulmonary arterial hypertension.
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PMID:The transforming growth factor-beta/Smad2,3 signalling axis is impaired in experimental pulmonary hypertension. 1739 19

Physiological responses to chronic hypoxia include polycythemia, pulmonary arterial remodeling, and vasoconstriction. Chronic hypoxia causes pulmonary arterial hypertension leading to right ventricular hypertrophy and heart failure. During pulmonary hypertension, pulmonary arteries exhibit increased expression of smooth muscle-alpha-actin and -myosin heavy chain. NFATc3 (nuclear factor of activated T cells isoform c3), which is aCa(2+)-dependent transcription factor, has been recently linked to smooth muscle phenotypic maintenance through the regulation of the expression of alpha-actin. The aim of this study was to determine if: (a) NFATc3 is expressed in murine pulmonary arteries, (b) hypoxia induces NFAT activation, (c) NFATc3 mediates the up-regulation of alpha-actin during chronic hypoxia, and (d) NFATc3 is involved in chronic hypoxia-induced pulmonary vascular remodeling. NFATc3 transcript and protein were found in pulmonary arteries. NFAT-luciferase reporter mice were exposed to normoxia (630 torr) or hypoxia (380 torr) for 2, 7, or 21 days. Exposure to hypoxia elicited a significant increase in luciferase activity and pulmonary arterial smooth muscle nuclear NFATc3 localization, demonstrating NFAT activation. Hypoxia induced up-regulation of alpha-actin and was prevented by the calcineurin/NFAT inhibitor, cyclosporin A (25 mg/kg/day s.c.). In addition, NFATc3 knock-out mice did not showed increased alpha-actin levels and arterial wall thickness after hypoxia. These results strongly suggest that NFATc3 plays a role in the chronic hypoxia-induced vascular changes that underlie pulmonary hypertension.
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PMID:NFATc3 mediates chronic hypoxia-induced pulmonary arterial remodeling with alpha-actin up-regulation. 1740 61

The metabolites of polychlorinated biphenyls (PCBs), such as hydroxylated PCBs (OH-PCBs), have been identified as environmental contaminants. Various studies have shown that some OH-PCBs can potentially contribute to health problems. Detection of these compounds in environmental and biological samples could provide useful information about their levels and lead to a better understanding of their apparent toxicity. To that end, we have developed a whole-cell sensing system for the detection of OH-PCBs by taking advantage of the recognition of a group of related compounds, i.e., hydroxylated biphenyls, by the product of the hbpR gene in the hbp operon from Pseudomonas azelaica strain HBP1. By fusing the luxAB genes, encoding the reporter protein bacterial luciferase, to the hbp regulator-promoter sequence, a whole-cell sensing system was developed. Here, we describe the optimization and application of this whole-cell sensing system for the detection of a model compound, 2-hydroxy-3',4'-dichlorobiphenyl. A detection limit of 1 x 10(-8) M was achieved using this system. The detection of a broad range of individual OH-PCBs as well as an OH-PCB mixture was investigated. The system can detect OH-PCBs in whole serum samples in a trace amount, which is comparable to the detection of these analytes in medium alone. We envision that the method developed can potentially be employed as a rapid and sensitive way to monitor OH-PCBs for toxicological study in the laboratory, as well as a useful tool to evaluate the presence of bioavailable OH-PCBs in natural environments.
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PMID:Hydroxylated polychlorinated biphenyl detection based on a genetically engineered bioluminescent whole-cell sensing system. 1760 71

Obesity is a complex, multifactorial chronic disease frequently associated with cardiovascular risks, hypertriglyceridemia, low high-density lipoprotein-cholesterol, high blood pressure, and the insulin resistance that appears to be central to the pathogenesis of Type II diabetes. Plasminogen activator inhibitor-1 expression induced in differentiating adipose tissue, but its role in adipogenesis and obesity is poorly understood. Circulating plasminogen activator inhibitor-1 levels are elevated at an early stage of impaired glucose tolerance, resulting in diabetes and metabolic syndrome. Plasminogen activator inhibitor-1 levels are also significantly elevated in the plasma of obese individuals and in adipose tissues of obese mice and humans. Some investigators proposed that the -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter caused overexpression of this gene and predisposed carriers to obesity. In this study, we investigated the role of -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter in the expression of this gene and the contribution of plasminogen activator inhibitor-1 to adipogenesis. Using a dual-luciferase promoter assay, we determined that the -675 4G/5G polymorphism contributes significantly to overexpression of plasminogen activator inhibitor-1 in the course of adipogenesis. The antidiabetic agents troglitazone and ciglitazone inhibited reporter gene expression driven by wild-type and -675 4G/5G mutant promoter, as well as the expression of endogenous plasminogen activator inhibitor-1, indicating that suppression of plasminogen activator inhibitor-1 expression may contribute to antidiabetic effects of these agents. The results indicate that absence of plasminogen activator inhibitor-1 in adipocytes may protect the cells against insulin resistance by promoting glucose uptake and adipocyte differentiation via a decrease in the peroxisome proliferator activated receptor-gamma expression that modulates the adipocyte differentiation.
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PMID:The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation. 1816 May 87

Guanylyl cyclase (GC)-A (natriuretic peptide receptor [NPR]-1), the receptor for atrial and brain natriuretic peptide, is important in the regulation of blood pressure in animal models and, possibly, in humans. In this study, we examined the association between dinucleotide repeat polymorphism within the 5'-flanking region of the GC-A gene and essential hypertension in a group of Japanese subjects. By genotyping 177 hypertensive and 170 normotensive subjects, we identified 5 allele types with 6, 9, 10, 11 and 12 CT dinucleotide repeats, respectively, around position -293, upstream of the ATG codon in the human GC-A gene. The frequency of the (CT)n=6 allele was significantly higher among hypertensive than normotensive subjects, while the frequencies of the other allele types did not differ between the two groups. We also examined the linkage between G/A polymorphism at position -77 (rs13306004), downstream of the (CT)n polymorphism, and found that the (CT)n=6 allele was tightly linked to an A at position -77, while all other (CT)n alleles were linked to G. Promoter-reporter analyses carried out in cultured human aortic smooth muscle cells using a luciferase gene fused to the 5'-flanking region of the GC-A gene revealed that the promoter containing (CT)n=6 drove less transcriptional activity than that containing (CT)n=10. Finally, site-directed mutation showed that the (CT)n and G/A polymorphisms act synergistically to affect GC-A promoter activity. Our results thus define the (CT)n polymorphism in the 5'-flanking region of the GC-A gene as a potent and novel susceptibility marker for hypertension.
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PMID:Association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase (GC)-A gene with essential hypertension in the Japanese. 1836 23

Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between -61 bp and +25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II-induced extracellular signal-regulated kinase phosphorylation, phosphorylation of extracellular signal-regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects.
Hypertension 2008 Jun
PMID:Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1. 1844 33

Endothelial cells have been shown to induce adrenal steroidogenesis and to enhance aldosterone secretion via angiotensin II and endothelin 1-independent mechanisms. It has been demonstrated that endothelial cells and adrenocortical cells are capable of producing interleukin-6 (IL-6) and IL-6 is a factor known to stimulate adrenal cortisol secretion. We therefore asked whether endothelial cells have an effect on adrenal IL-6 generation and whether IL-6 mediates biosynthesis of aldosterone as is observed after exposure of adrenocortical cells to endothelial cell-conditioned medium (ECCM). Cells from the adrenocortical cancer cell line NCI-H295R were incubated with ECCM produced from human umbilical vein endothelial cells at increasing concentrations. As detected by an enzyme-linked immunosorbent assay, pure ECCM significantly increased IL-6 protein secretion by cultured adrenocortical cells in a dose-dependent fashion, to a 18.0+/-2.0 pg/mL (mean+/-SEM). This was paralleled by an enhanced IL-6 promoter activity as determined with the transfection of an IL-6-promoter-luciferase reporter gene construct. Pure ECCM also induced aldosterone secretion by adrenocortical cells more than three times that of controls with serum-free medium. ECCM PER SE contains significant amounts of IL-6 protein. However, blockade of IL-6 signal transduction did not interfere with aldosterone synthesis. These data suggest that endothelial cells secrete IL-6 and that endothelial cell-derived factors regulate adrenal IL-6 synthesis which does not alter adrenal aldosterone secretion. Our findings support the hypothesis that the endothelium and the adrenal gland may play a role in the development of some forms of hypertension and - more speculative - inflammation.
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PMID:The endothelium secretes interleukin-6 (IL-6) and induces IL-6 and aldosterone generation by adrenocortical cells. 1877 60


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