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)

Glucocorticoid-induced ocular hypertension has been demonstrated in both animals and humans. It is possible that glucocorticoid-induced changes in trabecular meshwork (TM) cells are responsible for this hypertension. In order to elaborate further the effect of glucocorticoids on the trabecular meshwork, the ultrastructural consequences of dexamethasone (DEX) treatment were examined in three different human TM cell lines. Confluent TM cells were treated with 0.1 microM of DEX for 14 days, and then processed for light, epifluorescent microscopy or transmission electron microscopy (TEM). The effect of DEX treatment on TM cell and nuclear size was quantified using computer assisted morphometrics. Morphometric analysis showed a significant increase in both TM cell and nuclear size after 14 days of DEX treatment. Epifluorescent microscopy of rhodamine-phalloidin stained, control TM cells showed the normal arrangement of stress fibers. In contrast, DEX-treated TM cells showed unusual geodesic dome-like cross-linked actin networks. Control TM cells had the normal complement and arrangement of organelles as well as electron dense inclusions and large vacuoles. DEX-treated TM cells showed stacked arrangements of smooth and rough endoplasmic reticulum, proliferation of the Golgi apparatus, pleomorphic nuclei and increased amounts of extracellular matrix material. The DEX-induced alterations observed in the present study may be an indication of the processes that are occurring in the in vivo disease process.
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PMID:Dexamethasone induced ultrastructural changes in cultured human trabecular meshwork cells. 826 90

Vascular endothelium appears to be a unique organ. It not only responds to numerous hormonal and chemical signals but also senses changes in physical parameters such as shear stress, producing mediators that modulate the responses of numerous cells, including vascular smooth muscle, platelets, and leukocytes. In many cases, the initial response of endothelial cells to these diverse signals involves elevation of cytosolic Ca2+ and activation of Ca(2+)-dependent enzymes, including nitric oxide synthase and phospholipase A2. Both the release of Ca2+ from intracellular stores, most likely the endoplasmic reticulum, and the influx of Ca2+ from the extracellular space contribute to the [Ca2+]i increase. The most important trigger for Ca2+ release is inositol 1,4,5-trisphosphate, which is generated by the action of phospholipase C, a plasmalemmal enzyme activated in many cases by the receptor-G protein cascade. Ca2+ influx appears to be related to the activity of receptor-G protein-enzyme complex and to the degree of fullness of the endoplasmic reticulum but does not involve voltage-gated Ca2+ channels. The magnitude of the Ca2+ influx depends on the electrochemical gradient, which is modulated by the membrane potential, Vm. Under basal conditions, Vm is dominated by a large inward rectifier K+ current. Some stimuli, e.g., acetylcholine, have been shown to hyperpolarize Vm, thus increasing the electrochemical gradient for Ca2+, which appears to be modulated by activation of Ca(2+)-dependent K+ and Cl- currents. However, the lack of potent and specific blockers for many of the described or postulated channels (e.g., nonselective cation channel, Ca(2+)-activated Cl- channel) makes an estimation of their effect on endothelial cell function rather difficult. Possible future directions of research and clinical implications are discussed.
Hypertension 1993 Jan
PMID:Intracellular calcium, currents, and stimulus-response coupling in endothelial cells. 838 Feb 79

One of the changes in vascular smooth muscle membranes associated with hypertension is an alteration in Ca2+ handling. It has been unclear as to whether changes occurred at the plasma membrane or at the endoplasmic reticulum (ER) or both. Recently, cyclopiazonic acid (CPA) has been reported to inhibit selectively the ER Ca2+ pump. We aimed at determining the effect of ER Ca2+ pump inhibition by CPA on the contractility of aortic smooth muscle from 4- to 5-month-old SHR and age- and weight-matched WKY control rats. The responsiveness of the SHR tissues to phenylephrine or K+ was significantly reduced as compared with controls, although the sensitivity was not altered. Stimulation with phenylephrine (10 mumol/l) in Ca2(2+)-free medium caused a significantly reduced transient contraction in SHR as compared with control tissues. After pretreatment with CPA (30 mumol/l), this contraction was suppressed in SHR and WKY tissues. On the restoration of Ca2+, CPA induced a nifedipine (5 mumol/l) sensitive contraction, significantly larger in SHR than in WKY tissues. The relaxation rate to nifedipine of K(+)-induced contraction in CPA-treated SHR tissue was also reduced. We conclude that the ER Ca2+ pump in SHR aorta is less effective as compared with WKY tissue. The significantly greater CPA-induced contraction together with the reduced relaxation rate in the presence of CPA in SHR tissues as compared with controls suggests that Ca2+ handling was also altered at the plasma membrane.
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PMID:Functional alterations in the aorta of the spontaneously hypertensive rat: pharmacological assessment with cyclopiazonic acid. 839 93

The relationship between the Ca2+ transport of platelet endoplasmic reticulum and hypertension was analyzed in 17 untreated patients exhibiting various degrees of hypertension. Each patient underwent a 24-h recording of ambulatory blood pressure. Platelets from patients were permeabilized with saponin and the rate of ATP-driven thapsigargin-sensitive Ca2+ uptake determined using the fluorescent Ca2+ indicator fluo-3. No relationship between blood pressure (systolic, diastolic, day, night) and the rate of Ca2+ uptake into the sacroplasmic reticulum of platelets was found. A weak but insignificant correlation between Ca2+ uptake and the heart rate was noted. Therefore, the increase in cytosolic Ca2+ of platelets in hypertension may not be due to changes of the activity of Ca2+ uptake into the sacroplasmic reticulum.
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PMID:Hypertension does not affect intracellular calcium uptake in human platelets. 892 63

1. To obtain information about changes of basic fibroblast growth factor (bFGF) in the brain in chronic hypertension, we immunohistochemically studied the distribution and level of bFGF and its receptor in the brain of stroke-prone spontaneously hypertensive rats (SHRSP). 2. In the control normotensive rats, immunoreactivity for bFGF was demonstrated in nerve cells, while there was almost no reactivity in astrocytes. 3. In SHRSP, there was a marked immunoreactivity in the densely accumulated reactive cells, particularly astrocytes, in and around cerebral cortical lesions. Slightly increased reaction for bFGF was found in the nerve cells around lesions. Astrocytes in the subcortical white matter on both ipsi- and contralateral sides of the cortical lesion also showed immunoreactivity for bFGF. The location of increased bFGF expression in SHRSP corresponded very well with the site of extravasated plasma fluid demonstrated by anti-fibrinogen antibody. Electron microscopically, bFGF was shown in astrocytes along the rough endoplasmic reticulum suggesting the growth factor to be produced in the cells and not to be taken up from the surroundings. Expression of FGF-receptor was also demonstrated in reactive astrocytes in the oedematous cortical portion around lesion and in the oedematous subcortical white matter. 4. These findings indicate the possibility that oedema and the simultaneously generated free radicals or some extravasated plasma components express bFGF in astrocytes and probably in nerve cells as well as FGF-receptor in astrocytes, and that the thus expressed bFGF and its receptor play some role in the sequence of developmental events of hypertensive cerebral lesions.
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PMID:Increased immunoreactivities for the basic fibroblast growth factor and its receptor in astrocytes at the site of cerebral lesions and oedematous change in SHR. 907 83

The low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytic receptor with the ability to bind and endocytose several structurally and functionally distinct ligands. The 39 kDa receptor-associated protein (RAP) is an endoplasmic reticulum (ER) resident protein, which is believed to function intracellularly as a molecular chaperone for LRP and to regulate its ligand binding activity along the secretory pathway. Mouse heparin binding protein-44 (HBP-44) is a homologue of human RAP. Using a recombinant form of HBP-44 expressed in Escherichia coli cells as a highly specific ligand for LRP, we demonstrated that HBP-44 coated on cell culture plates mediates the cell-substratum adhesion of mouse 3T3 fibroblasts in a dose-dependent manner, with 50% attachment at the concentration of 0.2 micrograms/ml. Ligand blot analysis with HBP-44 of whole cell extracts and the materials precipitated by anti-LRP antibodies revealed that the receptor for HBP-44 on NIH/3T3 cells was LRP. The results suggest that LRP serves as a cell adhesion receptor in some cells.
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PMID:Heparin binding protein-44 (HBP-44)/receptor-associated protein (RAP)mediates cell-substratum adhesion of mouse NIH/3T3 cells through its binding to low density lipoprotein (LDL) receptor-related protein (LRP). 925 67

Abnormal vascular smooth muscle (VSMC) proliferation is a key feature in diabetes-associated atherosclerotic disease. Since nitric oxide inhibits VSMC tone, migration, adhesion, and proliferation, we examined the effects of high glucose on IL-1beta-induced NO release from VSMCs in culture. Confluent smooth muscle cells, preincubated with either 5 mmol/L (mM) or 20 mmol/L (mM) glucose for 48 hours, were stimulated with IL-1beta. Nitrite was measured in the culture medium after 24 hours. IL-1beta-induced a 15-fold increase in NO production in normal glucose medium. Glucose (10 to 30 mmol/L (mM)) significantly reduced the response to IL-1beta. High glucose (20 mmol/L (mM)) inhibited IL-1beta-evoked NO production by approximately 50%. IL-1beta-stimulated [3H] citrulline-forming activity of the nitric oxide synthase (NOS) was also significantly lower in high-glucose-exposed cells, and this was reflected in diminished cellular levels of NOS protein. To assess the role of protein kinase C (PKC), membrane PKC activity was measured, and glucose (20 mmol/L (mM)) significantly increased it. Immunoblotting of the membranes revealed a glucose-induced increase in the PKC betaII isoform. 1,2-Dioctanoyl-glycerol, a PKC activator, mimicked the high-glucose effect on IL-1beta-induced NO release, while staurosporine, a PKC inhibitor, reversed it. The role of calcium in the glucose-mediated inhibition of cytokine-induced NO release was determined by treatment with BAPTA, an intracellular chelator of calcium. BAPTA partially reversed the inhibitory effects of glucose. Increasing intracellular calcium by A23187, an ionophore or thapsigargin, an inhibitor of endoplasmic reticulum Ca2+-ATPase, significantly decreased IL-1beta-induced NO release and NOS expression. These results indicate that glucose-induced inhibition of IL-1beta-stimulated NO release and NOS expression may be mediated by PKC activation and increased intracellular calcium.
Hypertension 1998 Jan
PMID:Calcium and protein kinase C mediate high-glucose-induced inhibition of inducible nitric oxide synthase in vascular smooth muscle cells. 945 18

Platelet Ca2+ signalling involves intracellular Ca2+ pools, whose content is controlled by sarco/endoplasmic reticulum Ca2+ATPases (SERCAs). Among these, a key role is played by the inositol trisphosphate-sensitive Ca2+ pool, associated with the SERCA 3b isoform. We have investigated the control of this Ca2+ pool through the cAMP-dependent phosphorylation of the GTP-binding protein, Rap (Ras-proximate) 1b. We first looked for this Ca2+ pool target of regulation by studying the expression of the different SERCA and Rap 1 proteins in human platelets and various cell lines, by Western blotting and reverse transcription-PCR. Since co-expression of Rap 1b and SERCA 3b was obtained, we looked for their protein-protein interaction as a function of the cAMP-dependent phosphorylation of Rap 1b. Co-immunoprecipitations of SERCA 3b and Rap 1b proteins were found in the absence of phosphorylation, induced by the catalytic subunit of the cAMP-dependent protein kinase (csPKA). In contrast, upon pre-treatment of platelet membranes with csPKA, the SERCA 3b dissociated from the Rap 1b protein, in agreement with a role of its phosphorylated state in their interaction. Finally, we looked for adaptation of this complex in a platelet pathological model of hypertension. We investigated the expression of both proteins, as well as the cAMP-dependent phosphorylation of Rap 1b and SERCA 3b activity in platelets from control normotensive Wistar-Kyoto rats and from spontaneously hypertensive rats (SHRs). A decrease in SERCA 3b activity was associated with a decrease in Rap 1b endogenous phosphorylation in SHR platelets, consistent with a functional role in the regulation of the SERCA 3b-associated Ca2+ pool.
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PMID:Platelet sarco/endoplasmic reticulum Ca2+ATPase isoform 3b and Rap 1b: interrelation and regulation in physiopathology. 957 65

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

The epithelial Na+ channel (ENaC) is comprised of three homologous subunits: alpha, beta, and gamma, all of which are required for formation of the fully functional channel. This channel is responsible for salt reabsorption in the kidney, the airway, and the large bowel. Mutations in ENaC can cause human disease by increasing channel function in Liddle's syndrome, a form of hereditary hypertension, or by decreasing channel function in pseudohypoaldosteronism type I, a salt-wasting disease of infancy. We previously showed that ENaC is expressed on the cell surface as a minimally glycosylated, Triton-insoluble protein. In the present study we found that ENaC existed initially as a Triton-soluble protein that contained high-mannose glycosylation, presumably in the endoplasmic reticulum. This form of the protein disappeared as the Triton-insoluble, minimally glycosylated form became the more prevalent species. In pulse-chase studies of individually expressed subunits, we found that the Triton-soluble form of beta-ENaC accumulated initially, whereas the Triton-soluble form of alpha-ENaC decreased throughout the time course. However, when all three subunits were coexpressed, the alpha- and beta-subunits showed a similar pattern. The complex became Triton insoluble at some point after the endoplasmic reticulum, as incubation at 15 degrees C blocked the conversion to the insoluble form. Deletion of the carboxy-terminal tail of beta-ENaC causes Liddle's syndrome. This mutation increased the amount of newly synthesized Triton-insoluble ENaC heteromultimers but did not affect the half-life of insoluble protein. Therefore, subunit composition and mutations in individual subunits can influence biosynthesis of the ENaC complex.
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PMID:Effect of subunit composition and Liddle's syndrome mutations on biosynthesis of ENaC. 1036 97


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