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)

The aim of the present study was to assess the influence of the endothelial lipase (EL) gene 584C/T variant, which results in a change at codon 111 of the EL gene from threonine to isoleucine, on the risk of coronary artery disease (CAD) in a Chinese population. The study population consisted of 265 CAD patients and 265 age- and sex-matched control subjects. The T allele frequency was significantly lower among CAD patients than among control subjects (18.3% vs. 29.8%; P < 0.001). In both the CAD and control groups, the T allele carriers had higher high density lipoprotein cholesterol (HDL-C) levels than homozygote C allele carriers. In a multiple logistic regression model adjusted for age, sex, body mass index, smoking, hypertension, diabetes, hyperlipidemia, and low density lipoprotein cholesterol, a significantly decreased risk of developing CAD was found in subjects carrying a variant CT or TT genotype (odds ratio = 0.496, 95% confidence interval = 0.341-0.723; P < 0.001), and the significance persisted after further adjustment for HDL-C. In conclusion, our observation that the EL 584T allele was associated with protection from CAD in this Chinese population replicates the findings in a Japanese study, which found a similar association of this allele with acute myocardial infarction, independent of HDL-C levels.
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PMID:Protective effect of an endothelial lipase gene variant on coronary artery disease in a Chinese population. 1798 13

WNK kinases are a small group of unique serine/threonine protein kinases that are conserved among multicellular organisms. Mutations in WNK1-4 cause pseudohypoaldosteronism type II-a form of hypertension. WNKs have been linked to the STE20 kinases and ion carriers, but the underlying molecular mechanisms by which WNKs regulate cellular processes in whole animals are unknown. The Caenorhabditis elegans WNK-like kinase WNK-1 interacts with and phosphorylates germinal centre kinase (GCK)-3--a STE20-like kinase--which is known to inactivate CLH-3, a CIC chloride channel. The wnk-1 or gck-3 deletion mutation causes an Exc phenotype, a defect in the tubular extension of excretory canals. Expression of the activated form of GCK-3 or the clh-3 deletion mutation can partly suppress wnk-1 or gck-3 defects, respectively. These results indicate that WNK-1 controls the tubular formation of excretory canals by activating GCK-3, resulting in downregulation of CIC channel activity.
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PMID:Caenorhabditis elegans WNK-STE20 pathway regulates tube formation by modulating ClC channel activity. 1804 75

Nitric oxide (NO), generated from L-arginine by endothelial nitric oxide synthase (eNOS), is a key endothelial-derived factor whose bioavailability is essential to the normal function of the endothelium. Endothelium dysfunction is characterized by loss of NO bioavailability because of either reduced formation or accelerated degradation of NO. We have recently reported that overexpression of vascular cytochrome P-450 (CYP) 4A in rats caused hypertension and endothelial dysfunction driven by increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a major vasoconstrictor eicosanoid in the microcirculation. To further explore cellular mechanisms underlying CYP4A-20-HETE-driven endothelial dysfunction, the interactions between 20-HETE and the eNOS-NO system were examined in vitro. Addition of 20-HETE to endothelial cells at concentrations as low as 1 nM reduced calcium ionophore-stimulated NO release by 50%. This reduction was associated with a significant increase in superoxide production. The increase in superoxide in response to 20-HETE was prevented by N(G)-nitro-L-arginine methyl ester, suggesting that uncoupled eNOS is a source of this superoxide. The response to 20-HETE was specific in that 19-HETE did not affect NO or superoxide production, and, in fact, the response to 20-HETE could be competitively antagonized by 19(R)-HETE. 20-HETE had no effect on phosphorylation of eNOS protein at serine-1179 or threonine-497 following addition of calcium ionophore; however, 20-HETE inhibited association of eNOS with 90-kDa heat shock protein (HSP90). In vivo, impaired acetylcholine-induced relaxation in arteries overexpressing CYP4A was associated with a marked reduction in the levels of phosphorylated vasodilator-stimulated phosphoprotein, an indicator of bioactive NO, that was reversed by inhibition of 20-HETE synthesis or action. Because association of HSP90 with eNOS is critical for eNOS activation and coupled enzyme activity, inhibition of this association by 20-HETE may underlie the mechanism, at least in part, by which increased CYP4A expression and activity cause endothelial dysfunction.
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PMID:20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling. 1815 92

Mutations in mitochondrial DNA have been associated with hypertension. We report here the clinical, genetic, and molecular characterization of one four-generation Han Chinese family with hypertension. Two matrilineal relatives in this family exhibited the variable degree of a secondary hypertension (renal hypertension) at the age-at-onset of 42 and 56years old, respectively. Sequence analysis of the complete mitochondrial DNA in this pedigree revealed the presence of the known hypertension-associated ND1 T3308C mutation and 42 other variants, belonging to the Asian haplogroup D4h. The T3308C mutation resulted in the replacement of the first amino acid, translation-initiating methionine with a threonine in ND1. Furthermore, the ND3 T3308C mutation also locates in two nucleotides adjacent to the 3' end of mitochondrial tRNA(Leu(UUR)). Thus, this T3308C mutation caused an alteration on the processing of the H-strand polycistronic RNA precursors or the destabilization of ND1 mRNA. The occurrence of the T3308C mutation in these genetically unrelated pedigrees affected by diseases but absence of 242 Chinese controls as well as the mitochondrial dysfunctions detected in cells carrying this mutation indicate that this mutation is involved in the pathogenesis of hypertension. However, the mild biochemical defects, the lower penetrance of hypertension in this Chinese family and the presence of some control populations suggested the involvement of other modifier factors in the pathogenesis of hypertension associated with this ND1 T3308C mutation.
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PMID:The mitochondrial ND1 T3308C mutation in a Chinese family with the secondary hypertension. 1819 67

Sunitinib and sorafenib are both indicated for the treatment of advanced kidney carcinoma of the 'clear cell' type after failure of, or resistance to, other treatments. Both drugs inhibit the tyrosine-kinase activity of a number of growth factor receptors; sorafenib has an additional inhibitory effect on serine/threonine-kinase activity. This mechanism decreases signal transduction and results in an inhibition of tumour cell growth and angiogenesis. The adverse effects of the two drugs are different: sunitinib causes mainly fatigue and gastrointestinal discomfort, whereas sorafenib's most frequent adverse effects are diarrhoea, rash, the palmar-plantar erythrodysaesthesia syndrome, and hypertension.
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PMID:[New drugs; sunitinib and sorafenib]. 1836 11

The Rho-associated kinases (ROCKs) can regulate cell shape and function by modulating the actin cytoskeleton. ROCKs are serine-threonine protein kinases that can phosphorylate adducin, ezrin-radixin-moesin proteins, LIM kinase, and myosin light chain phosphatase. In the cardiovascular system, the RhoA/ROCK pathway has been implicated in angiogenesis, atherosclerosis, cerebral and coronary vasospasm, cerebral ischemia, hypertension, myocardial hypertrophy, and neointima formation after vascular injury. ROCKs consist of two isoforms: ROCK1 and ROCK2. They share overall 65% homology in their amino acid sequence and 92% homology in their amino kinase domains. However, these two isoforms have different subcellular localizations and exert biologically different functions. In particular, ROCK1 appears to be more important for immunological functions, whereas ROCK2 is more important for endothelial and vascular smooth muscle function. Thus, the ability to measure ROCK activity in tissues and cells would be important for understanding mechanisms underlying cardiovascular disease. This chapter describes a method for measuring ROCK activity in peripheral blood, tissues, and cells.
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PMID:A method for measuring Rho kinase activity in tissues and cells. 1837 65

The serine/threonine kinases ROCK1 and ROCK2 are direct targets of activated rho GTPases, and aberrant rho/ROCK signaling has been implicated in a number of human diseases. We have developed novel methods for high-throughput assays of ROCK inhibitors that provide for quantitative evaluation of the ability of small molecules to inhibit the function of ROCK kinases in intact cells. Conditions for extraction of known phosphorylated substrates of ROCK were identified, and the involvement of ROCK in phosphorylation of these substrates was evaluated using small interfering RNA (siRNA). Of the potential substrates tested, MYPT1 was identified as a substrate whose phosphorylation was reduced markedly in the combined absence of ROCK1 and ROCK2 proteins, and ELISA methods were developed to allow quantitative measurement of the degree of phosphorylation of MYPT1 at residue T853 in cells grown in 96-well plates. These methods are amenable to high-throughput assays for identification of ROCK inhibitors within libraries of small molecules and can be used to compare compound potencies to prioritize compounds of interest for additional evaluation. These methods should be useful in drug discovery efforts directed toward identifying potent ROCK inhibitors for potential treatment of cancer, hypertension, or other diseases involving rho/ROCK signaling.
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PMID:Quantitative high-throughput cell-based assays for inhibitors of ROCK kinases. 1837 84

Two members of a recently discovered family of protein kinases are the cause of an inherited disease known as pseudohypoaldosteronism type II (PHAII). These patients exhibit arterial hypertension together with hyperkalemia and metabolic acidosis. This is a mirror image of Gitelman disease that is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Na(+):Cl(-) cotransporter. The uncovered genes causing PHAII encode for serine/threonine kinases known as WNK1 and WNK4. Physiological and biochemical studies have revealed that WNK1 and WNK4 modulate the activity of several transport pathways of the aldosterone-sensitive distal nephron, thus increasing our understanding of how diverse renal ion transport proteins are coordinated to regulate normal blood pressure levels. Observations discussed in the present work place WNK1 and WNK4 as genes involved in the genesis of essential hypertension and as potential targets for the development of antihypertensive drugs.
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PMID:WNK kinases, renal ion transport and hypertension. 1854 46

WNK1 kinase belongs to a family of serine-threonine protein kinases with an atypical placement of the catalytic lysine. Increased expression of WNK1 causes hypertension and hyperkalemia in humans. WNK1 inhibits renal potassium channel ROMK1 by enhancing its endocytosis, likely contributing to hyperkalemia in affected patients. The domains of WNK1 involved in inhibition of ROMK1 have not been completely elucidated. Here, we reported that an NH2-terminal proline-rich domain (N-PRD; amino acids 1-119) is necessary and sufficient for WNK1 inhibition of ROMK1. A region (named "NL" for N-linker; amino acids 120-220) located between N-PRD and the kinase domain of WNK1 (amino acids 220-491) antagonized the inhibition of ROMK1 caused by N-PRD. The WNK1 kinase domain reversed the antagonism of NL on N-PRD. Mutagenesis studies revealed that charge-charge interactions between two conserved catalytic residues (Lys-233 and Asp-368) within the kinase domain (not the kinase activity) are critical for kinase domain to reverse the antagonism of NL domain. The WNK1 autoinhibitory domain (AID; amino acids 491-555) also affected ROMK, presumably by modulating the kinase domain conformation. Mutations of two conserved phenylalanine abolished the ability of AID to modulate ROMK1. Finally, the first coiled-coil domain (CC1; amino acids 555-640) of WNK1 alleviated the effect of AID domain toward kinase domain. Thus, multiple intra- and/or intermolecular interactions of WNK1 domains are at play for regulation of ROMK1 by WNK1.
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PMID:Domains of WNK1 kinase in the regulation of ROMK1. 1855 Jun 44

The Na(+):K(+):2Cl(-) cotransporter (NKCC2) is the target of loop diuretics and is mutated in Bartter's syndrome, a heterogeneous autosomal recessive disease that impairs salt reabsorption in the kidney's thick ascending limb (TAL). Despite the importance of this cation/chloride cotransporter (CCC), the mechanisms that underlie its regulation are largely unknown. Here, we show that intracellular chloride depletion in Xenopus laevis oocytes, achieved by either coexpression of the K-Cl cotransporter KCC2 or low-chloride hypotonic stress, activates NKCC2 by promoting the phosphorylation of three highly conserved threonines (96, 101, and 111) in the amino terminus. Elimination of these residues renders NKCC2 unresponsive to reductions of [Cl(-)](i). The chloride-sensitive activation of NKCC2 requires the interaction of two serine-threonine kinases, WNK3 (related to WNK1 and WNK4, genes mutated in a Mendelian form of hypertension) and SPAK (a Ste20-type kinase known to interact with and phosphorylate other CCCs). WNK3 is positioned upstream of SPAK and appears to be the chloride-sensitive kinase. Elimination of WNK3's unique SPAK-binding motif prevents its activation of NKCC2, as does the mutation of threonines 96, 101, and 111. A catalytically inactive WNK3 mutant also completely prevents NKCC2 activation by intracellular chloride depletion. Together these data reveal a chloride-sensing mechanism that regulates NKCC2 and provide insight into how increases in the level of intracellular chloride in TAL cells, as seen in certain pathological states, could drastically impair renal salt reabsorption.
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PMID:Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases. 1855 Aug 32


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