Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

For many years the simple view was held that contractile force in smooth muscle was proportional to cytosolic Ca2+ concentrations ([Ca2+]i). With the discovery that phosphorylation of myosin light chain by Ca2+/calmodulin-dependent myosin light chain kinase initiated contraction, regulation of the contractile elements developed more complex properties. Molecular and biochemical investigations have identified important domains of myosin light chain kinase: light chain binding sites, catalytic core, pseudosubstrate prototope, and calmodulin-binding domain. New protein phosphatase inhibitors such as okadaic acid and calyculin A should help in the identification of the physiologically important phosphatase and potential modes of regulation. The proposal of an attached, dephosphorylated myosin cross bridge (latch bridge) that can maintain force has evoked considerable controversy about the detailed functions of the myosin phosphorylation system. The latch bridge has been defined by a model based on physiological properties but has not been identified biochemically. Thin-filament proteins have been proposed as secondary sites of regulation of contractile elements, but additional studies are needed to establish physiological roles. Changes in the Ca2+ sensitivity of smooth muscle contractile elements with different modes of cellular stimulation may be related to inactivation of myosin light chain kinase or activation of protein phosphatase activities. Thus, contractile elements in smooth muscle cells are not dependent solely on [Ca2+]i but use additional regulatory mechanisms. The immediate challenge is to define their relative importance and to describe molecular-biochemical properties that provide insights into proposed physiological functions.
Hypertension 1991 Jun
PMID:Vascular smooth muscle contractile elements. Cellular regulation. 204 32

The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of hypertension in both organ transplant recipients and patients with autoimmune diseases. Despite the clinical importance of this hypertension, the underlying mechanisms have been enigmatic. This article presents a conceptual framework for understanding the pathophysiologic basis of CsA-induced hypertension and focuses on the hypothesis that a common molecular mechanism is involved in mediating the immunosuppressive and the hypertensive effects of CsA. This mechanism involves the binding of CsA to a newly discovered class of cytoplasmic receptors (termed "immunophilins") not only in T lymphocytes but also in the kidney, vascular smooth muscle, and central nervous system, which are the main target tissues mediating CsA-induced hypertension. Binding of CsA to its receptor leads to inhibition of calcineurin, the Ca2+/calmodulin-dependent protein phosphatase. Evidence is reviewed to support the hypothesis that calcineurin inhibition plays a pivotal role in mediating both CsA-induced immunosuppression and hypertension, the latter being produced at least in part by sympathetic neural activation. The elucidation of novel CsA-sensitive cellular signaling pathways has lead to the search for the ideal immunosuppressant drug, one which retains CsA's immunosuppressive efficacy but without its toxicity.
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PMID:Sympathetic neural mechanisms of cyclosporine-induced hypertension. 893 45

The S phase-specific expression of histone genes provides an interesting model for studying activation of gene transcription during the cell cycle. In plants, however, trans-acting factors responsible for histone gene transcription are poorly documented. Using combined gel shift, UV cross-linking and competition analysis, we carried out a systematic study to identify and characterize proteins binding with the previously established cis elements of the plant histone gene promoters. Nuclear extracts prepared from the highly synchronizable tobacco BY2 cells were used. We confirmed the presence of proteins binding to the hexamer (ACGTCA) motif which has been previously identified as the binding site of wheat HBP-1 proteins. Interestingly, multiple proteins were found to bind specifically with the nonamer (CAATCCAAC) element and their DNA-binding activity was abolished upon in vitro protein phosphatase treatment. This later result imply phosphorylation/dephosphorylation as a potential post-translational control for DNA-binding activity of nonamer-binding proteins. In addition, the DNA-binding activity of these nonamer-binding proteins was found to be positively correlated with the S phase-specific expression of the histone genes in the synchronized cells, suggesting their function in the activation of transcription during the G1/S transition. Finally, several proteins were observed to bind specifically with an A/T-rich hexamer (TAATAT) motif. Their DNA-binding activity, however, was insensitive to phosphatase activity in vitro and relatively constitutive during the cell cycle. This A/T-rich hexamer as a new cis-acting element of plant histone genes is discussed.
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PMID:Protein complexes binding to cis elements of the plant histone gene promoters: multiplicity, phosphorylation and cell cycle alteration. 904 59

A possible pathogenic polymorphism in the gene for the G subunit of the glycogen-associated regulatory form of protein phosphatase 1 (PP1 G subunit), causing an Asp-to-Tyr substitution at codon 905 (Asp905Tyr), has been reported to be associated with insulin resistance and hypersecretion of insulin in the white population. Since marked heterogeneity has been reported in the association of mutations of candidate genes with essential hypertension between Japanese and other ethnic groups, we investigated the association of Asp905Tyr with essential hypertension in Japanese subjects. The frequency of the Tyr allele in Japanese control subjects (0.70) was much higher than that in the Danish population (0.10, P<1x10(-8)), indicating that the Tyr allele, previously reported as a rare variant in white subjects, is a common allele in our population. The genotype distribution in Japanese hypertensive patients (n=109; Asp/Asp=0.09, Asp/Tyr=0.39, Tyr/Tyr=0.52) was not significantly different (chi2=0.7, df=2, P>.6) from that in normotensive control subjects (n=148; Asp/Asp=0.12, Asp/Tyr=0.36, Tyr/Tyr=0.52). Among subjects with different PP1 G subunit genotypes, there was no difference in blood pressure, serum cholesterol, plasma glucose and insulin levels, and glucose disposal rate estimated by the euglycemic hyperinsulinemic clamp test. These data indicate that the Asp905Tyr polymorphism of the PP1 G subunit is not associated with essential hypertension, nor with insulin resistance and/or hyperinsulinemia in Japanese patients with essential hypertension, suggesting that the polymorphism plays little if any role in susceptibility to insulin resistance or hypertension.
Hypertension 1997 Aug
PMID:Asp905Tyr polymorphism of protein phosphatase 1 G subunit gene in hypertension. 926 Sep 86

We studied by PCR-RFLP 6 polymorphisms in these 5 candidate genes: Ala54Thr in the fatty acid binding protein 2 gene (FABP2), A to G substitution in the uncoupling protein type 1 gene (UCP1), Asp905Tyr in the protein phosphatase type 1 gene (PP1G), Trp64Arg in the human beta 3 adrenergic receptor gene (beta 3AR) and 2 RFLP sites of the vitamin D receptor (VDR) gene (VDRTaq1 and VDRApa1). This study was conducted among 89 cases and 100 controls matched according to age, gender and absence of first degree family link (11 triplets with 2 controls for 1 case and 78 pairs with 1 control for 1 case). Cases and controls were taken among a sample of 429 individuals selected for the study of the prevalence of diabetes in this ethnic group from Guadeloupe. By conditional logistic regression analysis, there was a significant relation (p = 0.02) between the Ala54Thr FABP2 polymorphism and Type 2 DM. Multivariate analysis discriminate the FABP2 polymorphism (p = 0.10), a triglyceridemia over 2 g/l (p < 10(-3)) and high blood pressure (p = 10(-2)) as variables associated with Type 2 DM in this population. These findings suggest that FABP2 does not represent a major gene for Type 2 DM in this migrant Indian population living in Guadeloupe, but seems to be related to the metabolic insulin resistance syndrome.
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PMID:Type 2 diabetes mellitus: association study of five candidate genes in an Indian population of Guadeloupe, genetic contribution of FABP2 polymorphism. 1044 26

Na(+)/H(+) exchanger isoform-1 (NHE1), the ubiquitous form of the Na(+)/H(+) exchanger, has increased activity in hypertensive patients and in animal models of hypertension. Furthermore, NHE1 is activated in cells stimulated with growth factors. We showed previously that activation of the exchanger is dependent on phosphorylation of serine 703 (Ser(P)(703)) by p90 ribosomal S6 kinase (RSK). Because the NHE1 sequence at Ser(P)(703) (RIGSDP) is similar to a consensus sequence (RSXSXP) specific for 14-3-3 ligands, we evaluated whether serum stimulated 14-3-3 binding to NHE1. Five different GST-NHE1 fusion proteins spanning amino acids 515-815 were phosphorylated by RSK and used as ligands in a far Western analysis; only those containing Ser(P)(703) exhibited high affinity 14-3-3 binding. In PS127A cells (NHE1-overexpressing Chinese hamster fibroblasts) stimulated with 20% serum, NHE1 co-precipitation with GST-14-3-3 fusion protein increased at 5 min (5.2 +/- 0.4-fold versus control; p < 0.01) and persisted at 40 min (3.9 +/- 0.3-fold; p < 0.01). We confirmed that binding occurs at the RIGSDP motif using PS120 (NHE1 null) cells transfected with S703A-NHE1 or P705A-NHE1 (based on data indicating that 14-3-3 binding requires phosphoserine and +2 proline). Serum failed to stimulate association of 14-3-3 with these mutants. A GST-NHE1 fusion protein was phosphorylated by RSK and used as a ligand to assess the effect of 14-3-3 on protein phosphatase 1-mediated dephosphorylation of Ser(P)(703). GST-14-3-3 limited dephosphorylation (66% of initial state at 60 min) compared with GST alone (27% of initial state; p < 0.01). The protective effect of GST-14-3-3 was lost in the GST-NHE1 P705A mutant. Finally, the base-line rate of pH recovery in acid-loaded cells was equal in unstimulated cells expressing wild-type or P705A-NHE1. However, activation of NHE1 by serum was dramatically inhibited in cells expressing P705A-NHE1 compared with wild-type (0.13 +/- 0.02 versus 0.48 +/- 0.06 mmol of H(+)/min/liter, p < 0.01). These data suggest that 14-3-3 binding to NHE1 participates in serum-stimulated exchanger activation, a new function for 14-3-3.
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PMID:14-3-3 Binding to Na+/H+ exchanger isoform-1 is associated with serum-dependent activation of Na+/H+ exchange. 1127 64

The endothelial isoform of nitric-oxide synthase (eNOS) is a key determinant of vascular tone. eNOS, a Ca(2+)/camodulin-dependent enzyme, is also regulated by a variety of agonist-activated protein kinases, but the role and regulation of the protein phosphatase pathways involved in eNOS dephosphorylation are much less well understood. Treatment of endothelial cells with vascular endothelial growth factor (VEGF), a potent eNOS agonist, leads to the activation of calcineurin, a Ca(2+)/camodulin-dependent protein phosphatase. In these studies, we used a phosphorylation state-specific antibody to show that VEGF promotes dephosphorylation of eNOS at serine residue 116 in cultured endothelial cells. Cyclosporin A, an inhibitor of calcineurin, completely blocks VEGF-induced eNOS dephosphorylation; under identical conditions, cyclosporin A also inhibits VEGF-induced eNOS activation. VEGF-induced eNOS dephosphorylation shows an EC(50) of 2 ng/ml and is maximal 30 min after agonist addition. eNOS phosphorylation at serine 116 is completely blocked by the protein kinase C inhibitor calphostin but is blocked by neither wortmannin (an inhibitor of phosphatidylinositide 3-kinase) nor the MAP kinase pathway inhibitor U0126. A phosphorylation-deficient mutant of eNOS in which serine 116 is changed to an alanine residue (S116A) shows significantly enhanced enzyme activity compared with the wild-type enzyme. Taken together, these findings indicated that VEGF-induced eNOS dephosphorylation at serine 116 leads to enzyme activation. Cyclosporin A is widely used as an immunosuppressive drug for which hypertension is an important dose-limiting side effect. Our results suggest that cyclosporin A-induced hypertension may involve, at least in part, the attenuation of endothelium-derived NO production through a calcineurin-sensitive pathway regulating eNOS dephosphorylation.
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PMID:Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. 1205 Jan 71

Cardiac hypertrophy is induced by a variety of diseases, such as hypertension, valvular diseases, myocardial infarction, and endocrine disorders. Although cardiac hypertrophy may initially be a beneficial response that normalizes wall stress and maintains normal cardiac function, prolonged hypertrophy is a leading cause of heart failure and sudden death. A number of studies have elucidated molecules responsible for the development of cardiac hypertrophy, including the mitogen-activated protein (MAP) kinases pathway, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and calcium/calmodulin-dependent protein phosphatase calcineurin pathway. These molecules may be targets for therapies designed to prevent the progression of cardiac hypertrophy. Numerous studies have focused on characterization of the intracellular signal transduction molecules that promote cardiac hypertrophy in order to clarify the molecular mechanisms, but there have been only a few reports on the inhibitory regulators of hypertrophic response. Recently, several molecules have attracted much attention as endogenous inhibitory regulators of cardiac hypertrophy. Enhancement of these inhibitory regulators would also seem to be a potential approach for the pharmacological treatment of hypertrophy. In this review, we summarize the inhibitory molecules of cardiac hypertrophy.
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PMID:Inhibitory molecules in signal transduction pathways of cardiac hypertrophy. 1235 32

Insulin rapidly and completely inhibits expression of the hepatic insulin-like growth factor binding protein-1 (IGFBP-1), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes. This inhibition is mediated through a phosphatidyl inositol 3-kinase-dependent regulation of a DNA element, termed the thymine-rich insulin response element, found within the promoters of each of these genes. This has led to the conclusion that these three promoters are regulated by insulin using the same molecular mechanism. However, we recently found that the regulation of the IGFBP1 but not the PEPCK or G6Pase genes by insulin was sensitive to rapamycin, an inhibitor of mTOR. Here, we present further evidence that different regulatory pathways mediate the insulin regulation of these promoters. Importantly, we identify a protein phosphatase activity in the pathway connecting mTOR to the IGFBP-1 promoter. These data have major implications for the development of molecular therapeutics for the treatment of insulin-resistant states such as diabetes and hypertension.
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PMID:Different mechanisms are used by insulin to repress three genes that contain a homologous thymine-rich insulin response element. 1291 28

Peroxisome proliferator-activated receptor-gamma (PPARgamma), an orphan nuclear receptor, mediates adipocyte differentiation and is the cellular target for the thiazolidinedione group of insulin-sensitizing antidiabetic agents. We screened this receptor gene in a cohort of subjects with severe insulin resistance and have identified heterozygous missense mutations in several individuals from three families. Functional studies indicate that the receptor mutants are transcriptionally impaired and inhibit wild type PPARgamma action in a dominant-negative manner. The clinical phenotype of patients includes partial lipodystrophy, early-onset hypertension, dyslipidaemia and hepatic steatosis. Factors which contribute to the severe insulin resistance in affected individuals include diminished body fat mass, impaired lipid flux in adipose tissue and reduced circulating levels of adiponectin. In a large kindred of five individuals with severe insulin resistance, we have identified frameshift/premature stop mutations in PPARGAMMA; and the muscle-specific regulatory subunit of protein phosphatase 1 (PPP1R3A). The frameshift PPARgamma mutant exhibits complete loss of function with no dominant-negative activity; the PPP1R3A truncation mutant is mislocalized intracellularly. Individuals harbouring either gene defect alone have normal circulating insulin levels, but a combination of both genetic abnormalities co-segregates with severe insulin resistance.
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PMID:Peroxisome proliferator-activated receptor-gamma and insulin action: insights from human genetics. 1467 97


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