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

Uteroglobin (UG) is an anti-inflammatory/immunomodulatory protein. Targeted disruption of UG rendered mouse glomerulonephritis resembling immunoglobulin (Ig)A nephropathy (IgAN). Sequence analysis on exon 1 of UG showed several putative binding sites for transcription factors, and polymorphisms in this site might influence the expression level of UG as a competitive protein. We speculated that the single nucleotide polymorphism at the 38th nucleotide (A to G) from the transcription initiation site of UG exon 1 would impact the progression of IgA nephropathy (IgAN). Polymerase chain reaction-restriction fragment length polymorphism and single-strand conformation polymorphism were instituted to determine the genetic polymorphism. Luciferase assay was performed using the gene constructs containing a region 404-bp long located upstream of UG exon 1 initiation site to analyse whether this polymorphism would affect the expression level. UG polymorphism was distributed no differently in patients with IgAN (n = 111) compared to 60 healthy control subjects. An excess of A genotype was found in one patient having progressive disease (P = 0.03) and the risk for the disease progression increased as the number of A alleles increased (P for trend = 0.03) after follow-up for 116 months. The odds ratio for progression with the AA genotype was 4.9 (95% Cl = 1.0-23.9) compared to patients having the GG genotype. Significant interactive effects of hypertension and genetic polymorphisms of UG on the disease progression were observed (P for interaction = 0.001). In the luciferase assay, the gene construct with A at the 38th site showed a decreased activity of 74 +/- 8.4% compared to that showed by G gene construct. Our results suggest that polymorphism at the 5' UTR region of UG exon 1 is an important marker for the progression of IgAN and may modulate the level of protein expression.
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PMID:Uteroglobin gene polymorphisms affect the progression of immunoglobulin A nephropathy by modulating the level of uteroglobin expression. 1143 7

Knowledge of transcription and translation has advanced our understanding of cardiac diseases. Here, we present the hypothesis that the stability of mRNA mediated by the 3'-untranslated region (3'-UTR) plays a role in changing gene expression in cardiovascular pathophysiology. Several proteins that bind to sequences in the 3'-UTR of mRNA of cardiovascular targets have been identified. The affected mRNAs include those encoding beta-adrenergic receptors, angiotensin II receptors, endothelial and inducible nitric oxide synthases, cyclooxygenase, endothelial growth factor, tissue necrosis factor (TNF-alpha), globin, elastin, proteins involved in cell cycle regulation, oncogenes, cytokines and lymphokines. We discuss: (a) the types of 3'-UTR sequences involved in mRNA stability, (b) AUF1, HuR and other proteins that bind to these sequences to either stabilize or destabilize the target mRNAs, and (c) the potential role of the 3'-UTR mediated mRNA stability in heart failure, myocardial infarction and hypertension. We hope that these concepts will aid in better understanding cardiovascular diseases and in developing new therapies.
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PMID:The role of 3'-untranslated region (3'-UTR) mediated mRNA stability in cardiovascular pathophysiology. 1169

We conducted an association study between genetic variants of C-type natriuretic peptide gene (CNP) and hypertension in a Japanese population. We found four genetic variants, two in the promoter region, one missense mutation, and one in the 3'-untranslated region (3'-UTR), and genotyped all four variants in 2,006 subjects recruited from the Suita study. One of the variants, G2628A in 3'-UTR, was found to be associated with blood pressure. Multiple logistic analyses indicated that the genotype of the G2628A polymorphism (GG=1, GA+AA=2) (p=0.0034), sex (p=0.0288), alcohol consumption (p=0.0002), age (p<0.0001), and body mass index (p<0.0001) were predictors of hypertension. The odds ratio of the GA+AA genotype over the GG genotype for hypertension was 1.40 (p=0.0034, 95% confidence interval (CI) 1.12-1.75). Multiple logistic analyses in a younger subpopulation aged below 65 years indicated that the odds ratio of the GA+AA genotype over the GG genotype for hypertension was 1.58 (p=0.0024, 95%CI 1.18-2.12). Thus, the CNP G2628A polymorphism made an even greater contribution to hypertension in the younger subpopulation.
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PMID:A single-nucleotide polymorphism in C-type natriuretic peptide gene may be associated with hypertension. 1245 25

Natriuretic peptide system plays a well-defined role in the regulation of blood pressure and fluid volume. Although the effects of natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide) are mediated by specific biologic receptors, their plasma level is influenced by clearance receptors. It has been demonstrated that in hypertensive subjects plasma levels of natriuretic peptides are impaired; furthermore peptide receptor polymorphisms have been shown to be significantly associated with hypertension and cardiac hypertrophy. Studying normotensive subjects at high genetic risk of developing hypertension on the basis of family history makes it possible to investigate the role of natriuretic peptide system in the genesis of hypertension. It has been shown that plasma atrial and ventricular natriuretic peptide levels are significantly reduced in normotensive subjects with a family history of hypertension. Our study is the first one showing association among positive family history of essential hypertension and natriuretic peptide receptor polymorphisms. We identified a novel insertion/deletion polymorphism at position 15,129 in the 3'-untranslated region (3'-UTR) of NPRA receptor mRNA. The NPRA gene deletion variant is associated with hypertensive family history and higher systolic blood pressure. The "deletion 15129" variant might participate in the functional impairment of natriuretic peptide system defining an increased genetic susceptibility to hypertension.
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PMID:[Natriuretic peptides and essential arterial hypertension]. 1250 9

Hypertension and associated cardiovascular disease increase after menopause. Angiotensin AT(1) receptor (AT(1)R) antagonists are effective treatments, in part, by inhibiting angiotensin II (Ang II)-induced aldosterone release from the adrenal zona glomerulosa (ZG). Estrogen decreases the number of AT(1)Rs in the adrenal gland and attenuates acute Ang II-induced aldosterone release. Here, we examined the effects of 17beta-estradiol (E(2)) on AT(1)R gene regulation in the rat adrenal cortex (AC). Female rats were ovariectomized and injected with vehicle or E(2). Immunohistochemistry revealed the presence of both estrogen receptor (ER)alpha and ERbeta in the ZG, and E(2) treatment increased the intensity of their nuclear staining. Under conditions in which AT(1)R maximal binding capacity was decreased by 46%, chronic miniosmotic pump Ang II-induced aldosterone secretion was reduced by 43%. E(2) treatment had no effect on AT(1a)R and AT(1b)R mRNA levels in the AC, whereas the AT(1)R mRNA polysome distribution in sucrose gradients was shifted to lighter fractions, indicating that E(2) treatment reduces AT(1)R translation. RNA binding proteins (RBPs) in AC extracts formed complexes with the 5' leader sequence (5'LS), coding region, and the 3'-untranslated region (3'UTR); however, only the activity of 5'LS RBPs was regulated by E(2) treatment. These data suggest that E(2), acting through its receptors in the ZG, reduces AT(1)R density and Ang II-induced aldosterone release, primarily by inhibiting AT(1)R translation, possibly by blocking ribosomal scanning caused by increased steric hindrance from 5'LS RBPs. Dysregulation of this posttranscriptional mechanism may contribute to the increased incidence of cardiovascular disease associated with menopause.
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PMID:Estrogen regulates adrenal angiotensin AT1 receptors by modulating AT1 receptor translation. 1281 May 82

Endothelin-1 (ET-1) is known as a potent vasoconstrictor peptide and stimulator of cell proliferation. The human preproendothelin-1 mRNA contains a frequent adenine insertion polymorphism (allele frequency = 0.28) within the 5'-untranslated region (5'-UTR), 138 bp downstream of the transcription start site, which was assumed to be related to hypertension. This 5'-UTR variant could putatively influence the mRNA secondary structure and stability, efficacy of translation initiation, or binding of sequence-specific mRNA-binding proteins. By cloning the entire ET-1 gene 5'-UTR in a pGL3 vector and transfection of two cell lines, we studied the effects on luciferase expression in vitro. Luciferase activity was significantly increased in the insertion variant (I) compared to the wild-type (D) variant for both COS1 (2.97 +/- 0.12 versus 2.17 +/- 0.10; P = 0.002) and HepG2 cells (5.42 +/- 0.90 versus 3.68 +/- 0.37; P = 0.002). Investigations performed ex vivo using human umbilical vein endothelial cells were performed to examine the influence of genotypes on the formation of mRNA and protein. Preproendothelin-1-mRNA was quantified in relation to GAPDH by a realtime polymerase chain reaction. Homozygous I-carriers showed significant elevated mRNA levels compared to I/D and I/I-carriers (I/I 9.03 +/- 1.86, I/D 2.07 +/- 1.15, D/D 2.33 +/- 0.99; P = 0.001). ET-1 protein expression, determined by enzyme-linked immunosorbent assay, was increased among I-carriers (I/I 814 +/- 144, I/D 528 +/- 103, D/D 556 +/- 75 pg/ml; P = 0.001). The observed effects may be due to an enhanced mRNA stability because the half-life of mRNA consisting of the I-variant was prolonged (35.4 +/- 7.9 versus 19.9 +/- 4.5 min). We were able to show that the +138 I/D polymorphism is of functional importance for ET-1 expression, and this may have consequences for vessel tonus regulation.
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PMID:Functional significance of a hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene. 1289 81

The histone hairpin binding protein (HBP, also called SLBP, which stands for stem-loop binding protein) binds specifically to a highly conserved hairpin structure located in the 3' UTR of the cell-cycle-dependent histone mRNAs. HBP consists of a minimal central RNA binding domain (RBD) flanked by an N- and C-terminal domain. The yeast three-hybrid system has been used to investigate the critical residues of the human HBP involved in the binding of its target hairpin structure. By means of negative selections followed by positive selections, we isolated mutant HBP species. Our results indicate tight relationships between the RBD and the N- and C-terminal domains.
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PMID:Critical residues for RNA discrimination of the histone hairpin binding protein (HBP) investigated by the yeast three-hybrid system. 1470 61

Soluble guanylyl cyclase (sGC) is the only known receptor for nitric oxide (NO) and is downregulated in aging and hypertension. Little is known about sGC gene transcriptional regulation. In order to characterize the sGC transcriptional system, we cloned and sequenced the 5(') flanking region of mouse sGC alpha(1) gene (AY116663). Structurally, it is a non-canonical TATA-less promoter that we mapped to chromosome 3 with many putative regulation sites for Sp-1, NF-kappaB, and AP-1 transcription factors amongst others, and two (TG:CA)(n) dinucleotide microsatellites near the transcriptional start point. The cloned upstream sequence produced a 5-fold increase in luciferase activity in Cos7, HeLa, NIH3T3, and 293 cells as well as in mouse VSMC-like kidney mesangial cells. In the latter cell type, we showed that sGC alpha(1) promoter activity was dependent on the presence of its 5(') unstranslated region (5(')UTR).
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PMID:Molecular dissection of mouse soluble guanylyl cyclase alpha1 promoter. 1471 67

The role of A2350G polymorphism in exon 17 of the ACE gene and A1166C - in 3'-UTR of the AGTR1 in the pathogenesis of left ventricular hypertrophy was studied in patients with essential hypertension (EH) and arterial hypertension combined with diabetes mellitus type 2 (AH + DM2). Patients with EH and AH + DM2 did not differ from the control sample of healthy individuals by allele or genotype frequencies. However, an association of both polymorphisms with LVH was detected in EH patients. The frequency of 1166C allele was higher in patients with LVH (33.6% vs 20.7% without LVH). A1166C polymorphism determined the magnitude of left ventricular mass index (LVMI) in EH patients as well (p = 0.007). 2350G allele frequency of the ACE gene was in 1.5, and GG genotype--in 3.5-fold higher in EH patients with LVH, as compared without LVH. LVMI was significantly higher in patients with GG genotype as compared with heterozygotes and AA homozygotes (p = 0.002). Thus the presence of 1166C allele of AGTR1 and 2350G allele of ACE can be considered as predisposing factors for LVH development in EH. In contrast, association of studied polymorphisms with presence or LVH degree was not detected in patients with arterial hypertension combined with DM2. This may indicate another structure of genetic component of predisposition to LVH in different causes.
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PMID:[ACE and AGTR1 genes polymorphisms in left ventricular hypertrophy pathogenesis in humans]. 1561 84

Sympathetic hyper-innervation and increased levels of nerve growth factor (NGF), an essential neurotrophic factor for sympathetic neurons, have been observed in the vascular tissues of spontaneously hypertensive rats (SHRs). Such observations have suggested that the pathogenesis of hypertension might involve a qualitative or quantitative abnormality in the NGF protein, resulting from a significant mutation in the gene's promoter or coding region. In the present study, we analyzed the nucleotide sequences of the cis-element of the NGF gene in SHRs, stroke-prone SHRs (SHRSPs), and normotensive Wistar-Kyoto (WKY) rats. The present analyses revealed some differences in the 3-kb promoter region, coding exon, and 3' untranslated region (3'UTR) for the NGF gene among those strains. However, the observed differences did not lead to changes in promoter activity or to amino acid substitution; nor did they represent a link between the 3'UTR mutation of SHRSPs and elevated blood pressure in an F2 generation produced by crossbreeding SHRSPs with WKY rats. These results suggest that the NGF gene locus is not involved in hypertension in SHR/ SHRSP strains. The present study also revealed two differences between SHRs and WKY rats, as found in cultured vascular smooth muscle cells and in mRNA prepared from each strain. First, SHRs had higher expression levels of c-fos and c-jun genes, which encode the component of the AP-1 transcription factor that activates NGF gene transcription. Second, NGF mRNAs prepared from SHRs had a longer 3'UTR than those prepared from WKY rats. Although it remains to be determined whether these events play a role in the hypertension of SHR/SHRSP strains, the present results emphasize the importance of actively searching for aberrant trans-acting factor(s) leading to the enhanced expression of the NGF gene and NGF protein in SHR/SHRSP strains.
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PMID:No involvement of the nerve growth factor gene locus in hypertension in spontaneously hypertensive rats. 1602 43


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