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)

Recent studies suggest that the chemokine eotaxin may participate in atherosclerosis. Threonine (T) for alanine (A) substitution at amino acid 23 in the eotaxin gene (CCL11) has been associated with risk of developing allergic-inflammatory disorders. However, no genetic-epidemiological data are available on the risk of cardiovascular disease associated with this polymorphism. Using DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we evaluated the A23T polymorphism among 523 individuals who subsequently developed myocardial infarction (MI) and among 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. The T23 allele was significantly associated with risk of myocardial infarction (odds ratio (OR) in an age and smoking adjusted recessive model of inheritance, 1.86; 95% confidence interval (CI), 1.15-3.01; P = 0.012). This risk effect remained statistically significant in analyses further controlling for body mass index, history of hypertension, the presence of diabetes, and randomized treatment assignment (OR, 1.95; 95% CI, 1.19-3.18; P = 0.008). In this cohort, a T for A substitution at amino acid 23 in the eotaxin gene is associated with increased risk for incident myocardial infarction. If confirmed in other cohorts, these data support the emerging hypothesis that eotaxin participates in atherosclerosis.
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PMID:Threonine for alanine substitution in the eotaxin (CCL11) gene and the risk of incident myocardial infarction. 1518 51

The development of renin inhibitors for the treatment of hypertension requires highly sensitive substrates to evaluate potency and to characterize the mechanism of tight-binding inhibitors. A series of intramolecularly quenched fluorogenic renin substrates, based on the N-terminal tetradecapeptide sequence of human angiotensinogen (hTDP), was synthesized using a solid-phase technique. Incorporation of the fluorescent amino acid L-Amp [L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid] and the DNP (2,4-dinitrophenyl) group at various positions resulted in >90% quenching efficiency and strong product fluorescence. Shortening the hTDP sequence to an octapeptide from histidine in P5 to histidine in P3' (substrate 3) resulted in an acceptable k(cat)/K(m) (41000 M(-1).s(-1)) and further systematic variation gave substrate 9, DNP-Lys-His-Pro-Phe-His-Leu-Val-Ile-His-L-Amp, with a k(cat)/K(m) value of 350000 M(-1).s(-1) and 94% quenching efficiency. The free side chain of lysine, replacing the isoleucine residue at P6 position in the angiotensinogen sequence, contributed to the increased value for k(cat). The pH dependence of k(cat)/K(m) for renin and substrate 9 showed that the optimal pH is at pH 6-7. It also showed two titrating groups on the acidic side of the pH optimum, and one titrating group with a pK(a) of 7.8 on the alkaline side. The combination of good kinetic and spectroscopic properties resulted in a >20-fold improvement in the sensitivity of renin assay, compared with the commercial substrate Arg-Glu(EDANS)-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(DABCYL)-Arg [where EDANS is 5-[(2-aminoethyl)amino]naphthalene-1-sulphonic acid and DABCYL is 4-(4-dimethylaminophenylazo)benzoic acid] (k(cat)/K(m)=268000 M(-1) x s(-1), quenching efficiency <80%). The detection limit in a microplate renin assay was 60 pM, making substrate 9 well suited for the evaluation of inhibitors at picomolar concentrations.
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PMID:Highly sensitive intramolecularly quenched fluorogenic substrates for renin based on the combination of L-2-amino-3-(7-methoxy-4-coumaryl)propionic acid with 2,4-dinitrophenyl groups at various positions. 1523 25

WNK kinases comprise a small group of unique serine/threonine protein kinases that have been genetically linked to pseudohypoaldosteronism type II, an autosomal dominant form of hypertension. Here we present the structure of the kinase domain of WNK1 at 1.8 A resolution, solved in a low activity conformation. A lysine residue (Lys-233) is found in the active site emanating from strand beta2 rather than strand beta3 as in other protein kinases. The activation loop adopts a unique well-folded inactive conformation. The conformations of the P+1 specificity pocket, the placement of the conserved active site threonine (Thr-386), and the exterior placement of helix C, contribute to the low activity state. By homology modeling, we identified two hydrophobic residues in the substrate-binding groove that contribute to substrate specificity. The structure of the WNK1 catalytic domain, with its unique active site, may help in the design of therapeutic reagents for the treatment of hypertension.
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PMID:Crystal structure of the kinase domain of WNK1, a kinase that causes a hereditary form of hypertension. 1524 6

WNK (with no lysine [K]) protein kinases were named for their unique active site organization. Mutations in WNK1 and WNK4 cause a familial form of hypertension by undefined mechanisms. Here, we report that WNK1 selectively binds to and phosphorylates synaptotagmin 2 (Syt2) within its calcium binding C2 domains. Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells. Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change. These findings suggest that phosphorylation of Syts by WNK1 can regulate Ca2+ sensing and the subsequent Ca2+-dependent interactions mediated by Syt C2 domains. These findings provide a biochemical mechanism that could lead to the retention or insertion of proteins in the plasma membrane. Interruption of this regulatory pathway may disturb membrane events that regulate ion balance.
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PMID:WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding. 1535 Feb 18

WNK1 belongs to a unique family of Ser/Thr kinases that have been implicated in the control of blood pressure. Intronic deletions in the WNK1 gene result in its overexpression and lead to pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia. How overexpression of WNK1 leads to Na(+) retention and hypertension is not entirely clear. Similarly, there is no information on the hormonal regulation of expression of WNK kinases. There are two main WNK1 transcripts expressed in the kidney: the originally described "long" WNK1 and a shorter transcript that is specifically expressed in the kidney (KS-WNK1). The goal of this study was to determine the effect of aldosterone, the main hormonal regulator of Na(+) homeostasis, on the transcription of WNK1 isoforms in renal target cells, by using an unique mouse cortical collecting duct cell line that stably expresses functional mineralocorticoid receptors. Our results demonstrate that aldosterone, at physiological concentrations, rapidly induces the expression of the KS-WNK1 but not that of the long-WNK1 in these cells. Importantly, stable overexpression of KS-WNK1 significantly increases transepithelial Na(+) transport in cortical collecting duct cells. Similarly, coexpression of KS-WNK1 and the epithelial Na(+) channel in Fischer rat thyroid epithelial cells also stimulates Na(+) current, suggesting that KS-WNK1 affects the subcellular location or activity but not the expression of epithelial Na(+) channel. These observations suggest that stimulation of KS-WNK1 expression might be an important element of aldosterone-induced Na(+) retention and hypertension.
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PMID:The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport. 1558 31

Protein kinase C (PKC) is a member of a large family of serine/threonine kinases that plays an integral role in many of the signaling cascades that govern cellular behavior. As such, it is intricately involved in the processes that mediate disease pathogenesis. Strategies that serve to alter PKC function may prove to be useful in the treatment of numerous disease states. This article reviews the various roles PKC may play in cardiovascular disease, specifically with regard to ischemic heart disease, cardiac hypertrophy, heart failure, hypertension, and atherosclerosis, and suggests the potential for developing therapeutic approaches that can target PKC activity.
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PMID:Protein kinase C in cardiac disease and as a potential therapeutic target. 1559 21

Arterial hypertension is a complex trait influenced by a variety of environmental and genetic factors. Several approaches can be used to identify its susceptibility genes : one is to study rare monogenic forms of hypertension, like familial hyperkalemic hypertension (FHH). Also known as pseudohypoaldosteronism type 2 or Gordon syndrome, FHH is characterized by hypertension, hyperkalemia despite normal renal glomerular filtration rate, abnormalities which are particularly sensitive to thiazide diuretics. Mild hyperchloremia, metabolic acidosis, and suppressed plasma renin activity are associated findings. Despite its phenotypic and genetic heterogeneity, mutations in two related genes, WNK1 and WNK4, were recently identified. These genes belong to a newly identified family of serine-threonine (with no lysine [K]) kinases. Both are highly expressed in the kidney and in a variety of epithelia involved in chloride transport. It has thus been postulated that these two kinases could be implicated in a new pathway of ionic transport regulation. Several studies have very recently confirmed this hypothesis in vitro, in Xenopus oocytes or kidney cell lines. They have shown that, in the renal distal tubule, WNK4 inhibits sodium reabsorption and potassium secretion, via inhibition of NCC (thiazide-sensitive Na+-Cl- cotransporter) and K+ channel ROMK activity, respectively. Interestingly, FHH mutations have opposite effects : while they lead to loss of NCC inhibition, they increase ROMK inhibition. Moreover, they also increase paracellular permeability to chloride of MDCK cells. WNK4 also inhibits apical and basal chloride transporters present in extra-renal epithelia, such as CFEX and Na+-K+-2 Cl-, respectively. It is also interesting to note that the WNK4-mediated negative regulation of NCC activity is in turn inhibited by WNK1. By its role on several transporters, WNK4 appears as a putative key regulator of ionic transport and blood pressure.
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PMID:[WNK1 and WNK4, new players in salt and water homeostasis]. 1563 21

The WNK kinases are a recently discovered family of serine-threonine kinases that have been shown to play an essential role in the regulation of electrolyte homeostasis. Intronic deletions in the WNK1 gene result in its overexpression and lead to pseudohypoaldosteronism type II, a disease with salt-sensitive hypertension and hyperkalemia. This review focuses on the recent evidence elucidating the structure of the kinase domain of WNK1 and functions of these kinases in normal and disease physiology. Their functions have implications for understanding the biochemical mechanism that could lead to the retention or insertion of proteins in the plasma membrane. The WNK kinases may be able to influence ion homeostasis through its effects on synaptotagmin function.
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PMID:WNK1: analysis of protein kinase structure, downstream targets, and potential roles in hypertension. 1568 19

Key components of complex physiological regulatory pathways can be uncovered through the molecular-genetic study of rare, inherited diseases. WNK kinases are a recently discovered class of serine-threonine kinases that are distinctive because of the substitution of cysteine for lysine in subdomain II of the catalytic domain. Mutations in PRKWNK1 and PRKWNK4, which encode WNK1 and WNK4, result in an inherited syndrome of hypertension and hyperkalemia. Recent physiological work has revealed that WNK4 alters the balance of NaCl reabsorption and K(+) secretion in the distal nephron by actions on both transcellular and paracellular ion-flux pathways. Additionally, WNK4 is expressed in extra-renal epithelia with prominent roles in Cl(-) handling, and it regulates transporters that are responsible for Cl(-) flux across apical and basolateral membranes. WNK kinases are components of a novel signaling pathway that is important for the control of blood pressure and electrolyte homeostasis.
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PMID:Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch. 1580 6

1. Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke and renal failure. The incidence of hypertension is 25-30% in the adult Caucasian population and complications due to hypertension are even greater in African Americans. 2. The renin-angiotensin system plays an important role in the regulation of blood pressure and previous studies have suggested that angiotensinogen (AGT) gene locus is linked with human essential hypertension. Earlier studies suggested that a single nucleotide polymorphism (SNP) that converts methionine to threonine at amino acid 235 is associated with hypertension in the Caucasian population. However, this SNP is not associated with hypertension in African American and Chinese populations. 3. We have found an A/G polymorphism at -217 of the human AGT gene promoter and have shown that the frequency of allele A at -217 is significantly increased in the genomic DNA of African American hypertensive patients. 4. We have also shown that: (i) reporter constructs containing the AGT gene promoter with nucleoside A at -217 have increased promoter activity on transient transfection; and (ii) the CCAAT box enhancer binding protein (C/EBP) family of transcription factors and glucocorticoid receptor (GR) bind preferentially to this region of the promoter when nucleoside A is present at -217. In addition, variant -217A is always present with variants -532T, -793A and -1074T in the human AGT gene promoter. 5. These data suggest that the AGT haplotype containing -217A, -532T, -793A and -1074T may be involved in increased transcription of this gene and may play a role in human hypertension.
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PMID:A haplotype of the angiotensinogen gene is associated with hypertension in african americans. 1585 65


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