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

---

Query: EC:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

12/15-Lipoxygenase (LOX) activity is elevated in vascular diseases associated with impaired nitric oxide (( small middle dot)NO) bioactivity, such as hypertension and atherosclerosis. In this study, primary porcine monocytes expressing 12/15-LOX, rat A10 smooth muscle cells transfected with murine 12/15-LOX, and purified porcine 12/15-LOX all consumed *NO in the presence of lipid substrate. Suppression of LOX diene conjugation by *NO was also found, although the lipid product profile was unchanged. *NO consumption by porcine monocytes was inhibited by the LOX inhibitor, eicosatetraynoic acid. Rates of arachidonate (AA)- or linoleate (LA)-dependent *NO depletion by porcine monocytes (2.68 +/- 0.03 nmol x min(-1) x 10(6) cells(-1) and 1.5 +/- 0.25 nmol x min(-1) x 10(6) cells(-1), respectively) were several-fold greater than rates of *NO generation by cytokine-activated macrophages (0.1-0.2 nmol x min(-1) x 10(6) cells(-1)) and LA-dependent *NO consumption by primary porcine monocytes inhibited *NO activation of soluble guanylate cyclase. These data indicate that catalytic *NO consumption by 12/15-LOX modulates monocyte *NO signaling and suggest that LOXs may contribute to vascular dysfunction not only by the bioactivity of their lipid products, but also by serving as catalytic sinks for *NO in the vasculature.
...
PMID:Catalytic consumption of nitric oxide by 12/15- lipoxygenase: inhibition of monocyte soluble guanylate cyclase activation. 1142 23

The present investigation was undertaken to verify if the two nitric oxide synthase isoforms, eNOS and iNOS, are present in swine granulosa cells and whether the enzyme soluble guanylate cyclase is functionally active in the same cells and can account for NO effects. Using western blotting, the presence of endothelial NO synthase was demonstrated in freshly collected cells; on the contrary, iNOS expression was not observed in the same cells either before or after culture with the inflammatory cytokine hTNF-alpha. The treatment with a strong NO donor (S-Nitroso-L-acetyl penicillamine, SNAP) determined an increase of cGMP levels in culture media, which was attenuated by the combined treatment with an inhibitor of NO-sensitive soluble guanylate cyclase, 1H-[1,2,3]oxadiaziolo [4,3a]quinoxaline -1-one (ODQ). The cGMP analog, 8 bromo-cGMP, mimicked the strong inhibitory effect exerted by SNAP on estradiol 17 beta and progesterone production, while ODQ did not modify steroids concentrations in culture media. These observations demonstrate the presence of a follicular NO-generating system, which in swine granulosa cells seems to include only the endothelial NOS isoform. Furthermore, the nitric oxide/cyclic GMP system seems to be functionally active in these cells, since cGMP appears to mediate NO action, even if it cannot account completely for NO inhibitory effect on steroidogenesis.
...
PMID:Nitric oxide synthase expression and nitric oxide/cyclic GMP pathway in swine granulosa cells. 1151 18

Nitric oxide (NO) is a very small lipophilic molecule which rapidly diffuses and reaches the cytoplasmic components, and results in the activation of diverse biological function. It has been already reported that cultured osteoblasts synthesize NO in response to proinflammatory cytokines and lipopolysaccaride. In terms of the action of NO on bone metabolism, cytokine-induced NO by osteoblast inhibits bone resorption through inducing the apoptosis of osteoclast progenitor cells and suppressing the osteoclast activity. Also, NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine is reported to induce a dose-dependent inhibitory effect on the proliferation of osteoblast-like cell lines MG63 and ROS 17/2.8, which indicate that NO may stimulate cell proliferation. On the other hand, cytokine-induced NO is reported to reduce osteoblast activity significantly in high concentration, as was evidenced by inhibition of DNA synthesis, cell proliferation, alkaline phosphatase activity, and osteocalcin production. Thus, the effect of NO on osteoblast activities is still controversial. In the present study, S-nitroso-N-acetyl-dl-penicillamine(SNAP), NO donor enhanced DNA synthesis of MC3T3-E1 in vitro. This activation seems to be mediated by NO directly because specific NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) partially attenuated the osteoblast proliferation induced by SNAP. On the other hand, the guanylate cyclase inhibitor, LY83583, failed to abolish the effect of SNAP on DNA synthesis of osteoblasts and 8-bromo cyclic guanosine 3',5'-monophosphate(cGMP), substituting for the accumulation of intracellular cGMP in osteoblasts, did not enhance the incorporation of 3H-thymidine(3H-TdR). It is, then, suggested that osteoblast proliferation might be enhanced by NO independently apart from the activation of cytoplasmic guanylate cyclase and cGMP-dependent mechanisms.
...
PMID:Effect of nitric oxide on mouse clonal osteogenic cell, MC3T3-E1, proliferation in vitro. 1156 90

The ANP receptor is a single-transmembrane sequence receptor coupled to guanylate cyclase (GCase). It belongs to a family of GCase-coupled receptors that share a common overall molecular configuration. Collectively, theses GCase-coupled receptors belong to a larger family of single-transmembrane sequence receptors that include growth hormone and cytokine receptors. The signal transduction mechanism of these receptors has not been thoroughly understood. Receptor dimerization (or oligomerization) has been suggested as the mechanism. However, at least for the ANP receptor, dimerization has been seen to occur in the absence of the ligand, suggesting that an additional, as yet unknown effect of hormone binding is responsible for receptor activation. To understand the signaling mechanism, some of the functions and subsites of the ANP receptor critical for signaling have been identified, including the binding stoichiometry, receptor self-association, the juxtamembrane hinge structure containing a signature motif critical for GCase signaling, ANP-binding site residues, chloride-dependence of ANP binding, disulfide linkages, and glycosylation structures. These structures and the functional sites have been identified in the crystal structure of dimerized recombinant extracellular domain of the ANP receptor. The intracellular domain contains a kinase-homologous domain that regulates the activity of the GCase domain responding to ANP binding and also to binding of the allosteric effector ATP. Moreover, this regulatory role of the kinase-homologous domain is modulated by its own phosphorylated state. Although considerable data have been accumulated, the mechanism of ANP receptor signaling has not been well defined. Further studies are necessary to understand how ANP binds to the receptor, what conformational effect is caused by ANP binding, how this effect is transduced across the cell membrane, and how this transmembrane effect leads to stimulation of the GCase catalytic activity.
...
PMID:Natriuretic peptide receptor: structure and signaling. 1195 96

This study examined the role of nitric oxide (NO) in cytokine-induced apoptosis in adult cardiac fibroblasts (CFbs). In cultured adult rat CFbs, IL-1beta (5 ng/ml), but not interferon-gamma (10 ng/ml) or tumor necrosis factor-alpha (10 ng/ml), induced inducible NO synthase (iNOS) expression and NO production that was associated with an increase in caspase-3 activity and apoptotic cell death. Apoptotic frequency was reduced by the iNOS inhibitor S-methylisothiourea (3 x 10(-5) M). Apoptosis in response to IL-1beta was attenuated by the caspase-3 inhibitor [Z-Asp-Glu-Val-Asp-fluoromethyl ketone (Z-DVED-FMK)] but not by inhibition of guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). IL-1beta-induced CFb apoptosis was associated with an increase in p53 and Bax protein expression with no changes in Bcl-2 or Bcl-x(L). Nuclear condensation and fragmentation occurred when isolated nuclei were exposed to an NO donor [Z-1[N-(2-aminoethyl)-N-(2-ammonoethyl)amino]diazen-1-ium-1,2-dioate (DETA-NONOate) 10(-5) M], an effect that was not blocked by the peroxynitrite scavenger Mn(III)tetrakis(4-benzoic acid) porphyrin chloride. Moreover, Mn(III)tetrakis(4-benzoic acid) porphyrin chloride attenuated but did not eliminate IL-1beta-induced CFb apoptosis, indicating that the proapoptotic effect of NO can occur independently of its conversion to peroxynitrite. Our results demonstrate that IL-1beta-induced iNOS expression can trigger NO-dependent apoptosis in adult CFbs, which appears to result from DNA damage and may be mediated by a p53-dependent apoptotic pathway.
...
PMID:Mechanisms of cytokine induced NO-mediated cardiac fibroblast apoptosis. 1238 74

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in glomerulonephritis and nitric oxide (NO) exerts a variety of renal pathophysiological effects. We investigated the effect of exogenous NO on pro-inflammatory cytokine-induced MCP-1 expression in human mesangial cells and its signal transduction pathway. Cells were pretreated with NO donors such as 3-morpholino-sydnonimine (SIN-1) or nitroprusside, and then stimulated with tumor necrosis factor-alpha (TNF-alpha) or interleukin-1beta (IL-1beta). MCP-1 expression of mRNA and protein were measured by Northern blot analysis and ELISA. NF-kappaB binding activity was determined by electrophoretic mobility shift assay. Degradation of IkappaB-alpha protein was assessed by Western blot analysis. SIN-1 inhibited TNF-alpha- or IL-1beta-induced MCP-1 mRNA expression in a dose-dependent manner and also suppressed the MCP-1 protein expression. Nitroprusside inhibited the MCP-1 mRNA expression as well. SIN-1 dose dependently inhibited the TNF-alpha- or IL-1beta-induced NF-kappaB binding activity and suppressed the TNF-alpha-induced degradation of IkappaB-alpha. Analogue of cGMP (8-bromo-cGMP) had no significant effect on TNF-alpha-induced MCP-1 mRNA expression and guanylate cyclase inhibitor (ODQ) also had no significant influence on the inhibitory effect of SIN-1. These results suggest that exogenous NO inhibits MCP-1 expression via suppression of NF-kappaB by reducing the degradation of IkappaB-alpha and through a cGMP-independent pathway.
...
PMID:Exogenous nitric oxide inhibits tumor necrosis factor-alpha- or interleukin-1-beta-induced monocyte chemoattractant protein-1 expression in human mesangial cells. Role of IkappaB-alpha and cyclic GMP. 1239 21

Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) from the degradation of heme by the enzyme heme oxygenase. Because recent studies indicate that CO influences the properties of vascular SMCs, we examined whether this diatomic gas regulates apoptosis in vascular SMCs. Treatment of cultured rat aortic SMCs with a cytokine cocktail consisting of interleukin-1beta (5 ng/ml), tumor necrosis factor-alpha (20 ng/ml), and interferon-gamma (200 U/ml) for 48 hr stimulated apoptosis, as demonstrated by DNA laddering, caspase-3 activation, and annexin V staining. However, the exogenous addition of CO (200 ppm) completely blocked cytokine-mediated apoptosis. The antiapoptotic action of CO was partially reversed by the soluble guanylate cyclase inhibitor, H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 microM). In contrast, the p38 mitogen-activated protein kinase inhibitor, SB203580 (10 microM), had no effect on SMC apoptosis. These findings indicate that CO is a potent inhibitor of vascular SMC apoptosis and that it blocks apoptosis, in part, by activating the cGMP signaling pathway. The ability of CO to inhibit vascular SMC apoptosis may play a critical role in attenuating lesion formation at sites of arterial damage.
...
PMID:Antiapoptotic action of carbon monoxide on cultured vascular smooth muscle cells. 1270 89

Atrial natriuretic peptide (ANP) is a cardiovascular hormone secreted mainly by the cardiac atria and regulates the volume-pressure homeostasis. The action of ANP is mediated by its receptor, guanylyl cyclase-coupled receptor A (GC-A). In this study, we explored the possibility that ANP and GC-A may play a role in the dendritic cell (DC)-mediated immune regulation. We first examined the expression of GC-A in human monocyte-derived DCs in comparison with monocytes and found that DCs but not monocytes express GC-A at both the mRNA and protein levels. DCs responded to ANP with an increase in intracellular cGMP in a dose-dependent manner, indicating that GC-A expressed on DCs is functional. Furthermore, treatment of DCs with ANP decreased production of IL-12 and TNF-alpha and conversely increased that of IL-10 upon stimulation with LPS. In accordance with this change of cytokine production, DCs treated with ANP plus LPS promoted differentiation of naive CD4(+) T cells into a Th2 phenotype. Finally, we presented evidence that ANP affected cytokine production of fresh whole blood stimulated with LPS in line with the above-mentioned results. These results indicate that ANP polarizes human DCs toward a Th2-promoting phenotype through GC-A and thus can regulate immune responses.
...
PMID:Atrial natriuretic peptide polarizes human dendritic cells toward a Th2-promoting phenotype through its receptor guanylyl cyclase-coupled receptor A. 1279 12

Treatment of rat islets with the cytokine IL-1 results in the inhibition of mitochondrial function and insulin secretion, events that are mediated by beta-cell expression of iNOS [inducible nitric oxide (NO) synthase] and production of NO. beta-Cells recover from the inhibitory actions of NO, produced following 24 h incubation with IL-1, on islet oxidative metabolism and insulin secretion if iNOS enzymatic activity is inhibited and the islets are cultured (in the presence of IL-1 and iNOS inhibitors) for a brief period of 8 h. Islet recovery from cytokine- and NO-mediated damage is an active process that requires new gene expression, and NO itself is one activator of this recovery process. In this study, the mechanism by which NO stimulates islet recovery has been examined. Incubation of rat islets or RINm5F cells with the NO donor compound, sodium (Z)-1(N,N-diethylamino) diazen-1-ium-1,2-diolate (DEA-NO) for 1 h results in a 60% inhibition of mitochondrial aconitase activity. beta-Cells completely recover aconitase activity if the cells are washed to remove the NO donor compound and incubated for an additional 5 h in the absence of DEA-NO. The recovery of mitochondrial aconitase activity correlates with a 4-fold increase in cyclic GMP accumulation and is prevented by the inhibition of guanylate cyclase. The recovery of aconitase activity also correlates with the activation of members of the MAPKs, p38, c-Jun N-terminal kinase (JNK) and ERK, and the activation p38 and JNK is attenuated by inhibition of guanylate cyclase. ERK and p38 do not appear to participate in the recovery process as selective inhibition of these kinases fails to prevent recovery of aconitase activity; however, transduction of beta-cells with a dominant negative mutant JNK prevents beta-cell recovery from NO-mediated damage. These findings support a role for guanylate cyclase and JNK in the recovery of beta-cells from NO-mediated damage.
...
PMID:Role for c-Jun N-terminal kinase in beta-cell recovery from nitric oxide-mediated damage. 1286 20

Modulation of cytokine release may be of interest in modulating inflammatory diseases. This study determined whether nicorandil, a potassium channel opener, and nitric oxide (NO) donor could inhibit the release of tumour necrosis factor alpha (TNFalpha) from lymphocytes. Nicorandil significantly and dose-dependently inhibited the TNFalpha release from a human Epstein Barr virus-transformed B lymphocyte cell line (EBV-B) and peripheral blood B and T lymphocytes. The inhibition was reversed by the addition of both potassium channel inhibitor glibenclamide and the guanylyl cyclase inhibitor 1H-(1,2,4) oxadiazolo (4,3) quinoxalin-1-one (ODQ). Other potassium channel openers, pinacidil, or the nicorandil analogue SG-209, however, failed to demonstrate inhibition of TNFalpha release. The NO scavenger haemoglobin was unable to reverse the nicorandil-induced TNFalpha inhibition, but in contrast to this, sodium nitroprusside (SNP) partially inhibited the release, which was reversed by haemoglobin. Nicorandil is able to inhibit TNFalpha release from lymphocytes, which requires the dual modes of both potassium channel opening and the nitrate moiety. Moreover, NO donation mechanism appears to be more dominant in the nicorandil inhibitory activity in lymphocytes.The dual mechanism involved in the inhibition of this cytokines may represent a novel therapeutical approach in the modulation of inflammatory disease.
...
PMID:Nicorandil inhibits the release of TNFalpha from a lymphocyte cell line and peripheral blood lymphocytes. 1455 83


<< Previous 1 2 3 4 5 6 7 8 9 Next >>

---