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)

To clarify the role of PDGF A-chain in hypertensive vascular hypertrophy of spontaneously hypertensive rats (SHRs), we studied levels of PDGF A-chain gene expression and transcription factors related to the gene in vascular smooth muscle cells (VSMCs) of SHRs in vivo. RNase protection assay and in situ hybridization showed that PDGF A-chain mRNA levels in VSMCs of SHRs were twofold higher than in those of normotensive Wistar-Kyoto rats. Gel retardation assays showed that levels of Sp1 and AP-2 in VSMCs of SHRs were twofold more abundant than in those of Wistar-Kyoto rats. Treatment with four pharmacologically different species of antihypertensive drugs for 2 wk decreased the levels of both PDGF A-chain mRNA and Sp1, but not AP-2 level in VSMCs of SHRs with regression of aortic hypertrophy, indicating that increases in levels of both PDGF A-chain mRNA and Sp1 in VSMCs of SHRs were associated with high blood pressure. These results suggest that high blood pressure is a stimulus which upregulates PDGF A-chain gene expression in VSMCs of SHRs, resulting in an autocrine enhancement in hypertensive vascular hypertrophy, and that the activation of the gene may be mediated through increases in Sp1 in these cells.
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PMID:Blood pressure regulates platelet-derived growth factor A-chain gene expression in vascular smooth muscle cells in vivo. An autocrine mechanism promoting hypertensive vascular hypertrophy. 788 63

We investigated the transcriptional activity of the -131 to -92 region of the rat alpha2A-adrenergic receptor gene. In HT29 cells, this region has a positive effect on transcription, whereas in RINm5F cells, this region has a negative effect on transcription. The -131 to -92 region has a GC box (GGGGCGG) surrounded by overlapping GGAGG repeats. To analyze nuclear factor binding to this region, we made a series of sequence substitutions in the GGAGG repeats, the GC box, or both regions. Gel mobility shift assays indicated that most of the nuclear factor complexes formed between the wild-type -131/-92 sequence and either HT29 or RINm5F extracts were specific for SP1 or related proteins that recognize a GC box. Mutation of either the GGAGG repeats or the GC box did not eliminate the binding of Sp1 or related nuclear factors, suggesting that both the GGAGG repeats and the GC box could bind Sp1-related factors. Mutation of both these sites eliminated the binding of Sp1-related factors. In the absence of SP1 binding sites, this region had a negative effect on transcription in HT29 and a positive effect on transcription in RINm5F cells. These data support the notion that Sp1 and/or a related factor may control both positive and negative gene expression and suggest that the -131/-92 region may be involved in regulating tissue-specific levels of alpha2A-adrenergic receptor gene expression.
Hypertension 1996 Apr
PMID:Evidence for cell-specific regulation of transcription of the rat alpha2A-adrenergic receptor gene. 861 57

Studies on fibronectin, endothelin-1, and mortalin from our laboratory are reviewed here. Fibronectin expression has been analyzed as upregulated during in vitro serial passaging of human fetal lung and neonatal foreskin fibroblasts as well as umbilical vein endothelial cells. In vivo aging of skin fibroblasts, as well as aortic endothelial cells, are also accompanied by upregulation of fibronectin expression. Fibronectin promoter binding proteins from young and old cell nuclear extracts were further explored by gel retardation assay. Preliminary analyses have detected age-related differential binding activities with respect to AP-1, CRES, TFIID, CTF, and AP-2 regions, whereas Sp1 binding proteins remain unaltered. Endothelin-1 expression is also seen as upregulated during in vitro and in vivo aging of endothelial cells. This can contribute to the hypertension commonly observed in elderly patients. Mortalin, a novel member of hsp 70 family of proteins, was initially identified by virtue of its association with a cellular mortal phenotype. Subsequently, normal cells and the ones with an immortal phenotype have been found to have differential subcellular localization of this protein. Antiproliferative activity of this protein in normal cells and the deregulation of expression in transformed cells is observed which suggests the association of mortalin in pathways that determine cellular divisional phenotype.
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PMID:Expression of endothelin, fibronectin, and mortalin as aging and mortality markers. 908 6

The transcriptional regulatory mechanisms that control gene expression during differentiation and contractile protein accumulation are becoming well understood in skeletal and cardiac muscle lineages. Current understanding of smooth muscle-specific gene transcription is much more limited, though recent studies have begun to shed light on this topic. In this review, we summarize some of the themes emerging from these studies and identify transcriptional regulatory elements common to several smooth muscle genes. These include potential binding sites for serum response factor, Sp1, AP2, Mhox, and YY1, as well as a potential transforming growth factor-beta control element. We speculate that it may be possible to manipulate smooth muscle-specific gene expression in asthma or pulmonary arterial hypertension as an eventual therapy.
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PMID:Transcriptional regulation of smooth muscle contractile apparatus expression. 981 32

To elucidate if genetic variants in the bradykinin B2 receptor (B2) gene occur that could affect receptor expression and function, we screened for mutations in the promoter and in the coding region of the human B2 gene. In our initial study we analyzed 92 consecutive, unrelated subjects (including 25 patients with hypertrophic cardiomyopathy, 18 patients with dilated cardiomyopathy (DCM), 25 patients with hypertension, 18 patients with coronary heart disease, and 6 patients with valvular heart disease) using nonradioactive polymerase chain reaction-single-strand conformation polymorphism analysis as mutation screening method. We detected eight as yet unknown polymorphic sites in the promoter region of the B2 gene (-845 C/T, -704 C/T, -649 insG, -640 T/C, -536 C/T, -412 C/G, -143 C/T and -78 C/T) with allele frequencies between 0.5 and 13%. One of them (-412 C/G) destroys a Sp1 binding site and abolishes protein binding to this Sp1 site in human umbilical vein endothelial cells and human vascular smooth muscle cells. In the protein-coding region one new coding variant (T21M) with the potential to create a truncated receptor isoform was detected. We determined the frequency of the promoter variant at position -412 (C --> G) and the newly identified coding variant (T21M) in extended samples of 69 patients with HCM, 163 patients with DCM, 109 patients with hypertension, and 173 healthy anonymous blood donors. The promoter variant (-412 C/G) was found in one blood donor and the T21M mutation was not found in the control population. Therefore, it appears that these mutations are rare events and the determination of clinical significance will be a demanding task in the future.
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PMID:Screening the human bradykinin B2 receptor gene in patients with cardiovascular diseases: identification of a functional mutation in the promoter and a new coding variant (T21M). 988 Feb 21

Angiotensin (A) II plays a critical role in vascular remodeling, and its action is mediated by type 1 AII receptor (AT1R). Recently, 15-deoxy-(Delta)(12,14)-prostaglandin J(2) and thiazolidinediones have been shown to be ligands for peroxisome proliferator-activated receptor (PPAR)-gamma and activate PPAR-gamma. In the present work, we have studied the effect of PPAR-gamma on AT1R expression in rat vascular smooth muscle cells (VSMCs). We observed that: 1) endogenous AT1R expression was significantly decreased by PPAR-gamma ligands both at messenger RNA and protein levels, whereas AT1R messenger RNA stability was not affected; 2) AII-induced increase of (3)H-thymidine incorporation into VSMCs was inhibited by PPAR-gamma ligands; 3) rat AT1R gene promoter activity was significantly suppressed by PPAR-gamma ligands, and PPAR-gamma overexpression further suppressed the promoter activity; 4) transcriptional analyses using AT1R gene promoter mutants revealed that a GC-box-related sequence within the -58/-34 region of the AT1R gene promoter was responsible for the suppression; 5) Sp1 overexpression stimulated AT1R gene transcription via the GC-box-related sequence, which was inhibited by additional PPAR-gamma overexpression; 6) electrophoretic mobility shift assay suggested that Sp1 could bind to the GC-box-related sequence whereas PPAR-gamma could not; 7) antibody supershift experiments using VSMC nuclear extracts revealed that protein-DNA complexes formed on the GC-box-related sequence, which were decreased by PPAR-gamma coincubation, were mostly composed of Sp1; and 8) glutathione S-transferase pull-down assay revealed a direct interaction between PPAR-gamma and Sp1. Taken together, it is suggested that activated PPAR-gamma suppresses AT1R gene at a transcriptional level by inhibiting Sp1 via a protein-protein interaction. PPAR-gamma ligands, thus, may inhibit AII-induced cell growth and hypertrophy in VSMCs by AT1R expression suppression and possibly be beneficial for treatment of diabetic patients with hypertension and atherosclerosis.
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PMID:Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. 1141 35

The p22(phox) subunit is an essential protein in the activation of NAD(P)H oxidase. Here we report the preliminary characterisation of the human p22(phox) gene promoter. The p22(phox) promoter contains TATA and CCAC boxes and Sp1, gamma-interferon and nuclear factor kappaB sites. We screened for mutations in the p22(phox) promoter and identified a new polymorphism, localised at position -930 from the ATG codon, which was associated with hypertension. Mutagenesis experiments showed that the G allele had higher promoter activity than the A allele. These results suggest that the -930(A/G) polymorphism in the p22(phox) promoter may be a novel genetic marker associated with hypertension.
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PMID:Preliminary characterisation of the promoter of the human p22(phox) gene: identification of a new polymorphism associated with hypertension. 1272 92

1. Angiotensin II AT1A receptors are thought to play an important role in the development of hypertension. The transcriptional factor Sp1 is a ubiquitous transcriptional factor associated with GC-rich promoters and involved in basal promoter activity. 2. To examine basal transcriptional levels regulation of the rat AT1A receptor gene, we determined whether two GC-box-related regions within 100 bp of the rat AT1A receptor gene promoter are involved in the basal expression of the gene in A10 cells, a vascular smooth muscle cell line. 3. The electrophoretic mobility shift assay demonstrated that incubation of the -98/-79 region and -58/-34 region sequence oligonucleotides with nuclear extracts of rat hypothalamus, liver and adrenal formed DNA-protein complexes and that the addition of unlabelled oligonucleotides containing the Sp1 consensus sequence blocked the formation of the DNA-protein complex. The addition of antibody against Sp1 also blocked the formation of the DNA-protein complex. 4. The promoter/luciferase reporter assay demonstrated that the reporter activity of AT1A receptor promoters mutated either within the -98/-79 or the -58/-34 region was lower than that of intact AT1A receptor promoters. 5. The promoter activity of AT1A receptor promoters mutated within those two regions was lower than that of promoters mutated within either the -98/-79 or the -58/-34 region. 6. These findings suggest that GC-box-regulated sequences within the -98/-79 region and the -58/-34 region are additively involved in basal expression level of the AT1A receptor gene in A10 cells.
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PMID:Basal transcriptional regulation of rat AT1 angiotensin II receptor gene expression. 1475 91

Endothelial nitric oxide synthase (eNOS) plays an important role in maintaining blood pressure homeostasis and vascular integrity. Natural dietary flavoniods are thought to protect against cardiovascular diseases by acting as antioxidants and vasodilatants. This study examined the effect of cyanidin-3-glucoside (Cy3G), a typical anthocyanin pigment, on eNOS expression. Treatment of bovine artery endothelial cells (BAECs) with Cy3G for 8 hours of enhanced eNOS protein expression in a dose- and time-dependent manner was determined by Western blot analysis. Longer incubation (12, 16, and 24 hours) of BAECs with 0.1 micromol/L of Cy3G caused a further increase in eNOS expression, and subsequently Cy3G also significantly increased nitric oxide output 2-fold (24 hours). Furthermore, Cy3G stimulated the phosphorylation of Src and extracellular signal-regulated kinase 1/2 (ERK1/2) in a time-dependent manner. An Src kinase inhibitor, pp2, and MEK inhibitor, PD98059, blocked the ERK1/2 phosphorylation and eNOS expression. Transfection with dominant-negative Src cDNA also inhibited the eNOS expression stimulated by Cy3G. In addition, stimulation with Cy3G for 30 minutes resulted in a phosphorylation of Sp1 that was blocked by PD98059. Cy3G enhanced the binding activity of the transcription factor Sp1 to the GC box in the proximal eNOS promoter of BAECs, as revealed by chromatin immunoprecipitation assay. The present study demonstrated that Cy3G induced eNOS expression and escalated NO production via an Src-ERK1/2-Sp1 signaling pathway in vascular endothelial cells. Increased eNOS expression may help to ameliorate endothelial dysfunction, harmonize blood pressure, and prevent atherosclerosis as long-term beneficial effects of flavoniods.
Hypertension 2004 Aug
PMID:Upregulation of endothelial nitric oxide synthase by cyanidin-3-glucoside, a typical anthocyanin pigment. 1522 77

The type B natriuretic peptide receptor (NPR-B) is the cognate receptor for the C-type natriuretic peptide and, as such, is responsible for signaling growth-suppressant activity in vascular smooth muscle cells. Here we report the isolation and characterization of the human (h) NPR-B gene promoter. Using 5' rapid amplification of cDNA ends analysis, we have identified the 5' terminus of the hNPR-B gene transcript approximately 732 base pairs upstream from the presumed translation start site of the protein. We generated a series of 5' deletion mutants linked to a luciferase reporter and introduced these constructs into rat aortic smooth muscle cells or neonatal rat cardiac fibroblasts. Maximal expression was seen with a construct harboring 441 base pairs of 5' flanking sequence. Site-directed mutagenesis of the proximal promoter revealed a series of GC-rich sequences, 5 of which contributed modestly (approximately 25%) to basal hNPR-B promoter activity. Mutation of a sixth GC-rich sequence led to a >90% reduction in promoter activity. This sequence was shown to associate with Sp1 and Sp3 in vitro. The same mutation that resulted in loss of functional activity also resulted in loss of binding activity in vitro. Overexpression of Sp1 or Sp3 in Drosophila Schneider cells resulted in an increase in hNPR-B promoter activity that was completely nullified with the Sp1 binding site mutation described above. These studies provide the first description and characterization of the NPR-B gene promoter and suggest that this promoter's activity is dominated by a single cluster of Sp1-binding elements in the proximal 5' flanking sequence of the gene.
Hypertension 2004 Sep
PMID:Transcriptional regulation of type B human natriuretic Peptide receptor gene promoter: dependence on Sp1. 1526 9


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