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)

Angiotensin converting enzyme (ACE, EC 3.4.15.1) is a membrane-bound, zinc dependent dipeptidase that catalyzes the conversion of the decapeptide angiotensin I to the potent vasopressor ocatapeptide angiotensin II, by removing two C-terminal amino acids. ACE is well known as a key part of the renin angiotenisn system that regulates blood pressure, and its inhibitors have potential for the treatment of hypertension. This paper reviewed the characteristics of ACE in aspects of its structure-function relationship, gene polymorphism and inhibitor development. In particular, the catalytic mechanisms of the two active sites of somatic ACE in the cleavage of angiotensin I and bradykin are different. Therefore, it would likely provide a new way for exploiting novel ACE inhibitors with fewer side-effects by specifically-targeting the individual active sites of somatic ACE.
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PMID:[Structure and function of angiotensin converting enzyme and its inhibitors]. 1846 95

Dopaminergic and endothelin systems participate in the control blood pressure by regulating sodium transport in the renal proximal tubule. Disruption of either the endothelin B receptor (ETB) or D(3) dopamine receptor gene in mice produces hypertension. To examine whether these two receptors interact we studied the Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats by selectively infusing reagents into the right kidney of anesthetized rats. The D(3) receptor agonist (PD128907) caused natriuresis in WKY rats which was partially blocked by the ETB receptor antagonist. In contrast, PD128907 blunted sodium excretion in the SHRs. We found using laser confocal microscopy that the ETB receptor was mainly located in the cell membrane in control WKY cells. Treatment with the D(3) receptor antagonist caused its internalization into intracellular compartments that contained the D(3) receptors. Combined use of D(3) and ETB antagonists failed to internalize ETB receptors in cells from WKY rats. In contrast in SHR cells, ETB receptors were found mainly in internal compartments under basal condition and thus were likely prevented from interacting with the agonist-stimulated, membrane-bound D(3) receptors. Our studies suggest that D(3) receptors physically interact with proximal tubule ETB receptors and that the blunted natriuretic effect of dopamine in SHRs may be explained, in part, by abnormal D(3)/ETB receptor interactions.
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PMID:Renal D3 dopamine receptor stimulation induces natriuresis by endothelin B receptor interactions. 1875 91

Prolyl oligopeptidase (POP) is a serine protease that cleaves small peptides at the carboxyl side of an internal proline residue. Substance P, arginine-vasopressin, thyroliberin and gonadoliberin are proposed physiological substrates of this protease. POP has been implicated in a variety of brain processes, including learning, memory, and mood regulation, as well as in pathologies such as neurodegeneration, hypertension, and psychiatric disorders. Although POP has been considered to be a soluble cytoplasmic peptidase, significant levels of activity have been detected in membranes and in extracellular fluids such as serum, cerebrospinal fluid, seminal fluid, and urine, suggesting the existence of noncytoplasmic forms. Furthermore, a closely associated membrane prolyl endopeptidase (PE) activity has been previously detected in synaptosomes and shown to be different from the cytoplasmic POP activity. Here we isolated, purified and characterized this membrane-bound PE, herein referred to as mPOP. Although, when attached to membranes, mPOP presents certain features that distinguish it from the classical POP, our results indicate that this protein has the same amino acid sequence as POP except for the possible addition of a hydrophobic membrane anchor. The kinetic properties of detergent-soluble mPOP are fully comparable to those of POP; however, when attached to the membranes in its natural conformation, mPOP is significantly less active and, moreover, it migrates anomalously in SDS/PAGE. Our results are the first to show that membrane-bound and cytoplasmic POP are encoded by variants of the same gene.
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PMID:Characterization of membrane-bound prolyl endopeptidase from brain. 1865 87

Reactive oxygen species (ROS) including superoxide (O(2)(.-)) and hydrogen peroxide (H(2)O(2)) are produced endogenously in response to cytokines, growth factors; G-protein coupled receptors, and shear stress in endothelial cells (ECs). ROS function as signaling molecules to mediate various biological responses such as gene expression, cell proliferation, migration, angiogenesis, apoptosis, and senescence in ECs. Signal transduction activated by ROS, "oxidant signaling," has received intense investigation. Excess amount of ROS contribute to various pathophysiologies, including endothelial dysfunction, atherosclerosis, hypertension, diabetes, and acute respiratory distress syndrome (ARDS). The major source of ROS in EC is a NADPH oxidase. The prototype phagaocytic NADPH oxidase is composed of membrane-bound gp91phox and p22hox, as well as cytosolic subunits such as p47(phox), p67(phox) and small GTPase Rac. In ECs, in addition to all the components of phagocytic NADPH oxidases, homologues of gp91(phox) (Nox2) including Nox1, Nox4, and Nox5 are expressed. The aim of this review is to provide an overview of the emerging area of ROS derived from NADPH oxidase and oxidant signaling in ECs linked to physiological and pathophysiological functions. Understanding these mechanisms may provide insight into the NADPH oxidase and oxidant signaling components as potential therapeutic targets.
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PMID:NADPH oxidase-dependent signaling in endothelial cells: role in physiology and pathophysiology. 1878 13

The study of human monogenic diseases [pseudohypoaldosteronism type 1 (PHA-1) and Liddle's syndrome] as well as mouse models mimicking the salt-losing syndrome (PHA-1) or salt-sensitive hypertension (Liddle's syndrome) have established the epithelial sodium channel ENaC as a limiting factor in vivo in the control of ionic composition of the extracellular fluid, regulation of blood volume and blood pressure, lung alveolar clearance, and airway mucociliary clearance. In this review, we discuss more specifically the activation of ENaC by serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases are of critical importance in the activation of ENaC in different organs, such as the kidney, the lung, or the cochlea. Progress in understanding the basic mechanism of proteolytic activation of ENaC is accelerating, but uncertainty about the most fundamental aspects persists, leaving numerous still-unanswered questions.
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PMID:Activation of the epithelial sodium channel (ENaC) by serine proteases. 1892 7

Intraocular delivery of anti-vascular endothelial growth factor (VEGF) therapies is now used widely to treat age-related macular degeneration, and is currently undergoing evaluation in clinical trials for treatment of diabetic retinopathy. An important aspect of anti-VEGF treatment is that while the agents are injected into the vitreous cavity, they may be absorbed systemically, thus potentially affecting systemic VEGF levels. Systemic VEGF-A and the interplay between membrane-bound VEGF receptors and the soluble form of VEGF-R1 are key to angiogenesis, vasculogenesis, neurogenesis and hemodynamics. These cellular processes are regulated by complicated negative and positive feedback loops, many of which are disrupted and altered in diabetes. The VEGF protein, mRNA, as well as the actual VEGF receptor levels, appear to be impaired in diabetes in microvascular and macrovascular vessel beds. What is not clear is the exact role and influence that these levels have on an organ's function. In some organ systems, elevated VEGF levels act as a pathologic angiogenic stimulus (i.e., ocular neovascularization) whereas in others, low levels of VEGF activity leads to pathology (i.e., cardiomyopathy, wound healing and peripheral neuropathy). Diabetic patients have a higher risk of hypertension and proteinuria, two surrogate markers of systemic VEGF inhibition. Certain intraocular anti-VEGF treatments could therefore have an adverse effect in this population by possibly affecting circulating and organ-specific VEGF and VEGF receptor levels.
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PMID:Vascular endothelial growth factor and diabetic complications. 1892 76

Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-alpha-converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of gamma-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors.
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PMID:Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells. 1927 74

Pancreatic phospholipase A2 (phospholipase A2 group 1B, G1B) belongs to the superfamily of secreted phospholipase A2 (PLA2) enzymes. G1B has been proposed to be a potential target for diseases such as hypertension, obesity, and diabetes. Human pancreatic prophospholipase A2 (pro-hG1B) is activated by cleavage of the first seven-residue propeptide (phospholipase A2 propeptide, PROP). However, questions still remain on the mode of action for pro-hG1B. In this work, we expressed pro-hG1B in Pichia pastoris and determined the crystal structure at 1.55-A resolution. The x-ray structure demonstrates that pro-hG1B forms a trimer. In addition, PROP occupies the catalytic cavity and can be self-cleaved at 37 degrees C. A new membrane-bound surface and activation mechanism are proposed based on the trimeric model of pro-hG1B. We also propose a new autoproteolytic mechanism for pro-hG1B by the reaction triad Asp49-Arg0-Ser(-2) that is similar to the serine protease catalytic triad.
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PMID:Structural insight into the activation mechanism of human pancreatic prophospholipase A2. 1929 24

Tangier disease is a rare, autosomally inherited disorder of lipoprotein metabolism characterized by absence or marked deficiency of normal high density lipoprotein (HDL) cholesterol in plasma resulting in the accumulation of cholesterol esters in various organs. A 57-year old male with a past medical history of hypertension, coronary artery disease and splenectomy admitted to our hospital for rectal bleeding. In routine laboratory tests thrombocytopenia, hypocholesterolemia and low HDL levels were detected. Colonoscopy revealed 1-3 mm sized, brownish, spotty lesions spread throughout the colonic mucosa. Histopathologically accumulation of foam cells which showed lipid vacuoles and myeline figures on electron microscopy were observed. Bone marrow biopsy was also suggestive of lipid storage disease. The laparoscopic operation performed for acute cholecystitis showed similar appearances in the gall bladder and liver. The case was diagnosed as rare presentation of Tangier disease with gallbladder involvement in view of the low HDL cholesterol level and systemic lipid deposition.
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PMID:An unusual presentation of Tangier disease with gallbladder involvement. 1931 82

Fetal programming of adult disease is an area of research that has gained considerable attention. Epidemiological studies suggest that adverse intrauterine environment in fetal life is associated with a higher incidence of hypertension and coronary disease. Several mechanisms could contribute to these diseases and be regulated in a tissue-specific manner. The Na(+)-K(+)-ATPase, a membrane-bound enzyme, maintains the Na(+) and K(+) gradients across the plasma membrane of animal cells and therefore provides a mechanism for cell function regulation. Furthermore, in an in vitro model of cardiac hypertrophy, a decrease in the activity of the tricarboxylic acid (TCA) cycle enzyme, aconitase, was observed. We have shown that in our model of fetal programming, these two enzymes were regulated differently in heart and kidney of adult females.
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PMID:Renal and cardiac Na+-K +-ATPase and aconitase in a rat model of fetal programming. 1949 7


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