UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sarcoplasmic (or endoplasmic) reticulum Ca2+-ATPase (SERCA)-3 has been implicated in the possible dysregulation of Ca2+ homeostasis that accompanies the pathology of hypertension and diabetes. We report the molecular cloning of two alternatively spliced transcripts from the human SERCA3 gene, ATP2A3, that encode proteins that differ at their carboxy termini by 36 amino acids. SERCA3 transcripts were most abundantly expressed in lymphoid tissues, intestine, pancreas, and prostate. The two human SERCA3 proteins encoded by alternatively spliced transcripts were recognized by the monoclonal antibody PL/IM430 and demonstrated Ca2+ uptake and ATPase activity with an apparent Ca2+ affinity 0.5 pCa unit lower than that of other SERCA gene products. The subcellular distribution of SERCA3 protein was indistinguishable from that of SERCA2b, with expression in the nuclear envelope and in the endoplasmic reticulum throughout the cell. Two variant SERCA3 constructs, huS3-I and huS3-II, were isolated that encode proteins with three amino acid differences: Ala-673 (in huS3-I) substituted for Thr (in huS3-II), Ile-817 substituted for Met, and an insertion of Glu-994. huS3-I displayed a 10-fold lower capacity to transport Ca2+ than huS3-II.
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PMID:Functional characterization of alternatively spliced human SERCA3 transcripts. 984 5

Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.
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PMID:Signal transduction in arteriosclerosis: mechanical stress-activated MAP kinases in vascular smooth muscle cells (review). 985 3

Wilms' tumor is a childhood kidney tumor that is a striking example of the way that cancer may arise through development gone awry. A proportion of these tumors develop as a result of the loss of function mutations in the Wilms' tumor suppressor gene, WT1. Inherited mutations in the WT1 gene can lead to childhood kidney cancer, severe gonadal dysplasia, and life-threatening hypertension. Knockouts show that the gene is essential for the early stages of kidney and gonad formation. These tissues are completely absent in null mice. The WT1 gene encodes numerous protein isoforms, all of which share four zinc fingers. There is a large body of evidence supporting the notion that WT1 is a transcription factor, particularly a transcriptional repressor. Recently, however, we obtained evidence that WT1 colocalizes and is physically associated with splice factors. What is more, one alternative splice isoform of WT1 containing three amino acids, Lys-Thr-Ser (KTS; inserted between zinc fingers 3 and 4) is preferentially associated with splice factors, whereas the other alternative splice version, lacking these three amino acids, preferentially associates with the transcriptional apparatus. Both genetic and evolutionary considerations suggest that these two different forms of the protein have different functions. We will discuss recent evidence to further implicate WT1 in splicing. Our results raise the possibility that regulation of splicing is a crucial factor in the development of the genitourinary system, and that tumors may arise through aberrant splicing. To pursue the regulation and function of WT1 in whole animals, we have been introducing the human gene and large flanking regions cloned in yeast artificial chromosomes directly into mice. These studies have allowed us to dissect the function of WT1 at late as well as at early stages in organogenesis and to identify new sites and surprising new potential functions for the gene.
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PMID:Multiple roles for the Wilms' tumor suppressor, WT1. 1019 91

An alanine to threonine substitution at codon 54 of the fatty acid binding protein 2 (FABP2) gene has been associated with insulin resistance in Pima Indians and with obesity in aboriginal Canadians. We investigated whether this polymorphism contributes to obesity and insulin resistance in 258 Japanese subjects. Thirty-six subjects (13.9%) were homozygous for the Thr54 allele, 106 (41.1%) were heterozygous for the Ala54/Thr54 allele, and 116 (45.0%) were homozygous for the Ala54 allele. The frequency of the Thr54 allele was 0.34 and did not differ significantly between men and women. The incidence of non-insulin-dependent diabetes mellitus (NIDDM) was not different among the three genotypes. The variation at codon 54 of the FABP2 gene was not associated with obesity, hypertension, dyslipidemia, hyperuricemia, or hyperinsulinemia. These results suggest that the polymorphism at codon 54 of the FABP2 gene is not a major contributing factor to obesity and insulin resistance in Japanese subjects.
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PMID:Variation of the fatty acid binding protein 2 gene is not associated with obesity and insulin resistance in Japanese subjects. 1033 70

A missense gene mutation with methione-to-threonine amino acid substitution at codon 235 (M235T) of angiotensinogen (AGT) has been associated with higher plasma AGT levels and may influence the pathogenesis of cardiac hypertrophy and atherosclerosis. This study was undertaken to investigate the relationship of the M235T polymorphism of the AGT gene with left ventricular mass (LVM) and carotid intima-media thickness (IMT) in 175 Chinese patients with hypertension. The M235T mutation was detected by a mispairing primer method to create a BstUI restriction site in the polymerase chain reaction. The LVM was calculated with M-mode echocardiographic measures of the left ventricle. The IMT was measured in the common carotid and carotid bifurcation by B-mode ultrasound. Patients with the TT genotype (n = 106) were found to have significantly greater LVM index than those with the MM (n = 32) and MT (n = 37) genotypes (129.2 +/- 34.3 v 112.5 +/- 38.3 and 107.4 +/- 30.0 g/m2, P = .002), but the carotid IMT showed insignificant differences among three genotypic groups (1.320 +/- 0.703, 1.349 +/- 0.777, and 1.309 +/- 0.797 mm, P = .97). The M235T polymorphism (P = .004) was a significant predictor for LVM on multiple regression analysis, controlling all the potential confounding factors including age (P = .04), gender (P = .000), body mass index (P = .000), and so on, but the carotid IMT correlated only with age (P = .000), smoking (P = .02), and tissue plasminogen activator antigen (P = .02). These results indicated that the TT genotype of the AGT gene could be considered a risk factor for the development of cardiac hypertrophy, but not for carotid atherosclerosis in the hypertensive population.
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PMID:Left ventricular mass, carotid wall thickness, and angiotensinogen gene polymorphism in patients with hypertension. 1034 81

The contribution of genetic factors to hypertension in pregnancy, including pre-eclampsia, has been well documented. The association with a common molecular variant of the angiotensinogen (AGT) gene, in which methionine (M235) is substituted for threonine (T235) at residue 235, has been reported in both Caucasians and Japanese. In the present study, we examined 115 cases of pure type of hypertension in pregnancy (PHP) and 381 normal pregnant controls in order to look for subgroups in which the AGT gene is the major factor in the PHP pathogenesis. By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls. These results are discordant with those reported for Caucasian subjects where only a group of preeclamptic primigravidae was associated with the AGT variant, possibly indicating the existence of a racial difference. We also found that the variant frequency was significantly higher in the PHP subgroup with maternal age of 20-34 years (0.93) than in a subgroup of multigravid PHP patients age 35 years or older (0.77, P < 0.05) or in normal controls of age 20-34 years (0.76, P < 0.001). The result indicates that the AGT variant plays a significant role in hypertension in the age group 20-34 years.
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PMID:Association of a variant of the angiotensinogen gene with pure type of hypertension in pregnancy in the Japanese: implication of a racial difference and significance of an age factor. 1048 71

There are inconsistent reports that the angiotensinogen (ATG) variant Met235-->Thr (T235) allele and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) variants are associated with hypertension and related target organ damage. Both high blood pressure (BP) and abnormal diurnal BP variation patterns are related to target organ damage, but it is not known whether the above genetic variants of the renin-angiotensin system are related to 24 h BP and the diurnal BP pattern in Japanese. We studied the association of the ATG T235 allele and ACE D allele with 24 h BP and diurnal BP variation in 235 of 262 consecutive untreated (or off medication) elderly Japanese hypertensives who underwent 24 h ambulatory BP monitoring. There was no significant association between the T235 or ACE D allele with office BP, but the T235 allele was significantly associated with 24 h BP and day BP, and the D allele was significantly associated with increased 24 h BP, day BP, and night BP. There were no effects of the T235 or D alleles on any BP parameters. Those with white-coat hypertension had a significantly lower T235 allele frequency (0.68) than those with sustained hypertension (0.79, p=0.010), but the difference in D allele frequency was marginal (0.30 vs. 0.38, p=0.057). In conclusion, in elderly Japanese hypertensive individuals, both the ATG T 235 and ACE D alleles are associated with increased 24 h BP and day BP, while only the ACE D allele is associated with increased night BP.
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PMID:Angiotensinogen and angiotensin-converting enzyme genotypes, and day and night blood pressures in elderly Japanese hypertensives. 1048 25

Hemodynamic factors, circulating hormones, paracrine factors, and intracrine factors influence vascular smooth muscle growth and plasticity. The well-characterized role of angiotensin II in the modulation of vascular tone and cell function may be critically involved in the mechanisms by which vascular smooth muscle responds to signals associated with vascular endothelial dysfunction and increases in oxidative stress. Studies from this laboratory suggest that the trophic actions of angiotensin II may be intrinsically regulated by angiotensin-(1-7), a separate product of the angiotensin system derived from the common substrate, angiotensin I. Exposure of cultured vascular smooth muscle cells to angiotensin-(1-7) inhibited the trophic actions of angiotensin II and reduced the expression of the mitogenic effects of both normal serum and platelet-derived growth factor. The growth-inhibitory actions of angiotensin-(1-7) were blocked by the selective D-alanine(7)-angiotensin-(1-7) antagonist and the nonselective angiotensin receptor blocker sarcosine(1)-threonine(8)-angiotensin II. In contrast, subtype-selective antagonists for the AT(1) and AT(2) receptors had no effect on the inhibitory actions of angiotensin-(1-7), a finding that is consistent with the pharmacological characterization of a high-affinity (125)I-labeled angiotensin-(1-7) binding site in the vasculature by use of selective and nonselective angiotensin II receptor antagonists. The relevance of these findings to the proliferative response of vascular smooth muscle cells after endothelial injury was confirmed by assessment of the effect of a 12-day infusion of angiotensin-(1-7) on neointimal formation. In these experiments, the proliferative response produced by injuring the carotid artery was inhibited by angiotensin-(1-7) through a mechanism that could not be explained by changes in arterial pressure. Because plasma angiotensin-(1-7) increased to levels comparable to those found in animals and human subjects given therapeutic doses of angiotensin-converting enzyme inhibitors, angiotensin-(1-7) may be one factor participating in the reversal of vascular proliferation during inhibition of angiotensin II formation or activity.
Hypertension 1999 Oct
PMID:State-of-the-Art lecture. Antiproliferative actions of angiotensin-(1-7) in vascular smooth muscle. 1052 90

Somatostatin, a peptide with antisecretory and antiproliferative effects, coexists with noradrenaline in sympathetic neurons. Octreotide, a stable somatostatin analogue, prevents hypertension and cardiovascular structural changes induced by prolonged infusion of DPSPX (1,3-dipropyl-8-sulfophenylxanthine, a non-selective adenosine receptor antagonist) in rats. In the present work we investigated the effect of somatostatin and its analogue octreotide on the release of [(3)H]noradrenaline from sympathetic nerves in the rat mesenteric artery. Rat mesenteric arteries were incubated for 60 min with [(3)H]noradrenaline (0.2 microm), mounted in perifusion chambers, washed out for 90 min and electrically stimulated (2 Hz, 5 min, 50 mA). Radioactivity was measured in the tissue and in the perifusion fluid before, during and after stimulation. Both somatostatin and octreotide inhibited tritium release evoked by electrical stimulation of in vitro preparations of rat mesenteric arteries preloaded with [(3)H]noradrenaline. The maximal effects produced by octreotide and somatostatin were a 56 and 70% inhibition of noradrenaline release, respectively. For somatostatin an EC(50)=0. 18 n m (0.01 n m-2.2 n m;n =16) was calculated. When used alone, the somatostatin receptor antagonist, cyclo(7-aminoheptanoyl-Phe- d -Trp-Lys-Thr[BZL]) (CYCAM; 1 microm), had no effect on noradrenaline release induced by electrical stimulation. However, it was able to significantly antagonize the inhibitory effects of octreotide and somatostatin. These results are compatible with a negative modulatory role of somatostatin on sympathetic neurotransmission.
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PMID:Somatostatin inhibits the release of noradrenaline induced by electrical stimulation of the rat mesenteric artery. 1070 76

Maternal protein deficiency during pregnancy is associated with changes in glucose tolerance and hypertension in the offspring of rats. In this study the growth of rat fetuses was examined when the dams were fed diets containing 18% casein, 9% casein or 8% casein supplemented with threonine. The extra threonine was added to reverse the decrease in circulating threonine concentrations that occurs when pregnant rats are fed protein-deficient diets. The fetuses of the group fed the low protein diet supplemented with threonine were significantly smaller than those of the control group and not significantly different from those fed low protein. Homogenates prepared from the livers of dams fed the diet containing 9% casein oxidized threonine at approximately twice the rate of homogenates prepared from dams fed the diet containing 18% casein. We conclude that circulating levels of threonine fall as a consequence of an increase in the activity of the pathway that metabolizes homocysteine produced by the transulfuration of methionine. Serum homocysteine was unaffected in the dams fed low protein diets compared with controls, but was significantly greater in dams fed the low protein diet supplemented with threonine. Elevated levels of homocysteine are associated with changes in the methylation of DNA. The endogenous methylation of DNA was greater than that of controls in the livers of fetuses from dams fed the 9% protein diets and increased further when the diet was supplemented with threonine. Our results suggest that changes in methionine metabolism increase homocysteine production, which leads to changes in DNA methylation in the fetus. An increase in maternal homocysteine may compromise fetal development, leading to the onset of glucose intolerance and hypertension in adult life.
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PMID:Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. 1086 57

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