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

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

Reactive nitrogen species are thought to be involved in both hypoxic-ischemic and cytokine-induced brain injury, including periventricular leukomalacia (PVL), the major pathological substrate of cerebral palsy in premature infants. PVL appears to be the result of perinatal inflammatory events and hypoxic-ischemic injury to the cerebral white matter. The chronic disturbance of myelination resulting from PVL suggests that developing oligodendrocytes (OLs) are involved in its pathogenesis. We hypothesized that nitric oxide (NO) could participate in the pathogenesis of PVL through a toxic effect on developing OLs. Using primary cultures of highly enriched OLs we found that NO is toxic to developing OLs (O4+, O1-, MBP-), with an EC50 value of 236 +/- 125 microm of DETANOnoate. Peroxynitrite formation does not appear to be involved in NO toxicity in developing OLs, as determined by the failure of peroxynitrite scavengers as well as superoxide dismutase overexpression to prevent NO-induced toxicity. Similarly, several pathways involving PARP, excitotoxicity, guanylyl cyclase and caspase activation were not related to NO toxicity to developing OLs. NO toxicity to OLs resulted in ATP depletion and loss of mitochondrial membrane potential (DeltaPsi) in developing OLs. Apoptosis-inducing factor (AIF) has been shown to be involved in caspase-independent cell death, and we found that AIF translocated from mitochondria into the nucleus upon NO exposure. In conclusion, we suggest that the vulnerability of developing OLs to NO involves mitochondrial dysfunction and translocation of AIF from mitochondria to nuclei.
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PMID:Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. 1537 92

The trace element zinc affects several aspects of immune function, such as the release of proinflammatory cytokines from monocytes. We investigated the role of cyclic nucleotide signaling in zinc inhibition of LPS-induced TNF-alpha and IL-1beta release from primary human monocytes and the monocytic cell line Mono Mac1. Zinc reversibly inhibited enzyme activity of phosphodiesterase-1 (PDE-1), PDE-3, and PDE-4 in cellular lysate. It additionally reduced mRNA expression of PDE-1C, PDE-4A, and PDE-4B in intact cells. Although these PDE can also hydrolyze cAMP, only the cellular level of cGMP was increased after incubation with zinc, whereas cAMP was found to be even slightly reduced due to inhibition of its synthesis. To investigate whether an increase in cGMP alone is sufficient to inhibit cytokine release, the cGMP analogues 8-bromo-cGMP and dibutyryl cGMP as well as the NO donor S-nitrosocysteine were used. All three treatments inhibited TNF-alpha and IL-1beta release after stimulation with LPS. Inhibition of soluble guanylate cyclase-mediated cGMP synthesis with LY83583 reversed the inhibitory effect of zinc on LPS-induced cytokine release. In conclusion, inhibition of PDE by zinc abrogates the LPS-induced release of TNF-alpha and IL-1beta by increasing intracellular cGMP levels.
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PMID:Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-alpha and IL-1 beta production in monocytes by elevation of guanosine 3',5'-cyclic monophosphate. 1617 17

Monocyte-to-macrophage differentiation with the cytokine granulocyte-macrophage colony-stimulating factor induces expression of the cyclic nucleotide phosphodiesterase PDE1B2. However, what role PDE1B2 plays in macrophage biology has not been elucidated. We have addressed this question by inhibiting PDE1B2 induction by using RNA interference. Using a retrovirus-based system, we created HL-60 stable cell lines that express a short-hairpin RNA targeting PDE1B2. HL-60 cells treated with phorbol-12-myristate-13-acetate differentiate to a macrophage-like phenotype and up-regulate PDE1B2. However, expression of PDE1B2 short hairpin RNA effectively suppresses PDE1B2 mRNA, protein, and activity up-regulation. Using the HL-60 PDE1B2 knockdown cells and agonists for either adenylyl or guanylyl cyclase, it was found that PDE1B2 predominantly regulates cGMP and plays a lesser role in cAMP regulation in response to cyclase agonists. Furthermore, in intact HL-60 cells, PDE1B2 activity can be regulated by changes in Ca+2 levels. Inhibiting PDE1B2 up-regulation does not prevent HL-60 cell differentiation, because several markers of macrophage differentiation are unaffected. However, suppression of PDE1B2 expression alters some aspects of the macrophage-like phenotype, because cell spreading, phagocytic ability, and CD11b expression are augmented. The cAMP analog 8-Bromo-cAMP reverses the changes caused by PDE1B2 knockdown. Also, PDE1B2 knockdown cells have lower basal levels of cAMP and alterations in the phosphorylation state of several probable PKA substrate proteins. Thus, the effects of PDE1B2 on differentiation may ultimately be mediated through decreased cAMP. In conclusion, PDE1B2 regulates a subset of phenotypic changes that occur upon phorbol-12-myristate-13-acetate-induced differentiation and likely also plays a role in differentiated macrophages by regulating agonist-stimulated cGMP levels.
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PMID:PDE1B2 regulates cGMP and a subset of the phenotypic characteristics acquired upon macrophage differentiation from a monocyte. 1640 68

Nitric oxide (NO), applied by inhalation or released from NO donors, has been used to reduce the expression of cell adhesion molecules (CAM) and ameliorate other consequences of ischemia/reperfusion (I/R) injury. In this study, we have assessed the time frames of pretreatment and of the duration of the preconditioned state using human umbilical vein endothelial cells (HUVECs) and the NO donor, SNAP, in combination with cysteine. The induction of vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM) and E-selectin by the cytokines TNFalpha and IL-1beta, and by bacterial lipopolysaccharide (LPS) was reduced by SNAP/Cys preincubation (30 min, 1mM) to less than 10% of controls. This refractory state in respect to cytokine-induced CAM expression persisted for 6h after washout of the NO donor in the combination TNFalpha/VCAM, and a partial block was still observed after 8h. The effect was not mediated by the cGMP pathway, as was demonstrated by using the inhibitor of guanylyl cyclase, ODQ, and the cGMP analogue, 8-Br-cGMP. The TNFalpha-induced expression of CAM was exclusively dependent on the transcription factor NFkappaB since the inhibitor of NFkappaB activation, BAY 11-7082, completely blocked the induction. The TNFalpha-induced phosphorylation and degradation of the inhibitor of kappaB (IkappaBalpha) was suppressed for up to 8h after SNAP/Cys pretreatment. The inhibitory S-nitrosation of IkappaB kinase (IKKbeta), as assessed by the biotin-switch-procedure and immunoprecipitation, was only detectable immediately after SNAP/Cys incubation but not at later time points. In summary, a short preincubation of HUVEC with SNAP/Cys results in a persistent suppression of NFkappaB-dependent expression of CAM. The stabilization of IkappaBalpha over the same time span may be causally related to this effect.
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PMID:Nitric oxide donor-induced persistent inhibition of cell adhesion protein expression and NFkappaB activation in endothelial cells. 1650 56

Th2 lymphocytes differ from other CD4+ T lymphocytes not only by their effector tasks but also by their T cell receptor (TCR)-dependent signaling pathways. We previously showed that dihydropyridine receptors (DHPR) involved in TCR-induced calcium inflow were selectively expressed in Th2 cells. In this report, we studied whether cGMP-dependent protein kinase G (PKG) activation was implicated in the regulation of DHPR-dependent calcium response and cytokine production in Th2 lymphocytes. The contribution of cGMP in Th2 signaling was supported by the following results: 1) TCR activation elicited cGMP production, which triggered calcium increase responsible for nuclear factor of activated T cell translocation and Il4 gene expression; 2) guanylate cyclase activation by nitric oxide donors increased intracellular cGMP concentration and induced calcium inflow and IL-4 production; 3) reciprocally, guanylate cyclase inhibition reduced calcium response and Th2 cytokine production associated with TCR activation. In addition, DHPR blockade abolished cGMP-induced [Ca2+]i increase, indicating that TCR-induced DHP-sensitive calcium inflow is dependent on cGMP in Th2 cells. Th2 lymphocytes from PKG1-deficient mice displayed impaired calcium signaling and IL-4 production, as did wild-type Th2 cells treated with PKG inhibitors. Altogether, our data indicate that, in Th2 cells, cGMP is produced upon TCR engagement and activates PKG, which controls DHP-sensitive calcium inflow and Th2 cytokine production.
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PMID:The cGMP/protein kinase G pathway contributes to dihydropyridine-sensitive calcium response and cytokine production in TH2 lymphocytes. 1653 16

In the study of anti-proinflammation by 7-[2-[4-(2-chlorobenzene)piperazinyl] ethyl]-1,3-dimethylxanthine (KMUP-1) and 7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-3), exposure of rat tracheal smooth muscle cells (TSMCs) to tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, increased the expression of inducible nitric-oxide synthase (iNOS) and NO production and decreased the expression of soluble guanylate cyclase alpha1 (sGCalpha1), soluble guanylate cyclase beta1 (sGCbeta1), protein kinase G (PKG), and the release of cGMP in TSMCs. The cell-permeable cGMP analog 8-Br-cGMP, xanthine-based KMUP-1 and KMUP-3, and the phosphodiesterase 5 inhibitor zaprinast all inhibited TNF-alpha-induced increases of iNOS expression and NO levels and reversed TNF-alpha-induced decreases of sGCalpha1, sGCbeta1, and PKG expression. These results imply that cGMP enhancers could have anti-proinflammatory potential in TSMCs. TNF-alpha also increased protein kinase A (PKA) expression and cAMP levels, cyclooxygenase-2 (COX-2) expression, and activated productions of prostaglandin (PG) E2 and 6-keto-PGF1alpha (stable PGI2 metabolite). Dexamethasone and N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398; a selective COX-2 inhibitor) attenuated TNF-alpha-induced expression of COX-2 and activated productions PGE2 and PGI2. However, KMUP-1 and KMUP-3 did not affect COX-2 activities and did not further enhance cAMP levels in the presence of TNF-alpha. It is suggested that TNF-alpha-induced increases of PKA expression and cAMP levels are mediated by releasing PGE2 and PGI2, the activation products of COX-2. In conclusion, xanthine-based KMUP-1 and KMUP-3 inhibit TNF-alpha-induced expression of iNOS in TSMCs, involving the sGC/cGMP/PKG expression pathway but without the involvement of COX-2.
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PMID:Inhibition of proinflammatory tumor necrosis factor-{alpha}-induced inducible nitric-oxide synthase by xanthine-based 7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine (KMUP-1) and 7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1, 3-dimethylxanthine (KMUP-3) in rat trachea: The involvement of soluble guanylate cyclase and protein kinase G. 1675 82

Inflammatory activation of glial cells is associated with neuronal injury in several degenerative movement disorders of the basal ganglia, including manganese neurotoxicity. Manganese (Mn) potentiates the effects of inflammatory cytokines on nuclear factor-kappaB (NF-kappaB)-dependent expression of nitric oxide synthase 2 (NOS2) in astrocytes, but the signaling mechanisms underlying this effect have remained elusive. It was postulated in the present studies that direct stimulation of cGMP synthesis and activation of mitogen-activated protein (MAP) kinase signaling pathways underlies the capacity of Mn to augment NF-kappaB-dependent gene expression in astrocytes. Exposure of primary cortical astrocytes to a low concentration of Mn (10 microM) potentiated expression of NOS2 mRNA and protein along with production of NO in response to interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), which was prevented by overexpression of dominant negative IkappaB alpha. Mn also potentiated IFNgamma- and TNFalpha-induced phosphorylation of extracellular response kinase (ERK), p38, and JNK, as well as cytokine-induced activation of a fluorescent NF-kappaB reporter construct in transgenic astrocytes. Activation of ERK preceded that of NF-kappaB and was required for maximal activation of NO synthesis. Independently of IFNgamma/TNFalpha, Mn-stimulated synthesis of cGMP in astrocytes and inhibition of soluble guanylate cyclase (sGC) abolished the potentiating effect of Mn on MAP kinase phosphorylation, NF-kappaB activation, and production of NO. These data indicate that near-physiological concentrations of Mn potentiate cytokine-induced expression of NOS2 and production of NO in astrocytes via activation of sGC, which promotes ERK-dependent enhancement of NF-kappaB signaling.
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PMID:Manganese potentiates nuclear factor-kappaB-dependent expression of nitric oxide synthase 2 in astrocytes by activating soluble guanylate cyclase and extracellular responsive kinase signaling pathways. 1833 17

The benzylindazole derivative 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) is an allosteric stimulator of soluble guanylate cyclase (sGC) that sensitizes the enzyme to the gaseous ligands carbon monoxide (CO) and nitric oxide (NO). In this study, we examined whether YC-1 also promotes the production of these gaseous monoxides by stimulating the expression of the inducible isoforms of heme oxygenase (HO-1) and NO synthase (iNOS) in vascular smooth muscle cells (SMCs). YC-1 increased HO-1 mRNA, protein, and promoter activity and potentiated cytokine-mediated expression of iNOS protein and NO synthesis by SMCs. The induction of HO-1 by YC-1 was unchanged by the sGC inhibitor, 1H-(1,2,4)oxadiazolo[4,3-alpha]quinozalin-1-one (ODQ) or by the protein kinase G inhibitors (8R,9S,11S)-(-)-2-methyl-9-methoxyl-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo(a,g)cyclocta9(cde)trinen-1-one (KT 5823) and YGRKKRRQRRRPPLRKKKKKH-amide (DT-2) and was not duplicated by 8-bromo-cGMP or the NO-independent sGC stimulator 5-cyclopropyl-2[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b] pyridine-3-yl] pyrimidin-4-ylamine (BAY 41-2272). However, the YC-1-mediated induction of HO-1 was inhibited by the phosphatidylinositol-3-kinase (PI3K) inhibitors wortmannin and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002). In contrast, the enhancement of cytokine-stimulated iNOS expression and NO production by YC-1 was prevented by ODQ and the protein kinase A inhibitor (9S,10S, 12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9, 12-epoxy-1H-diindolo(1,2,3-fg:3',2',1'-kl)pyrrolo(3,4-i)(1,6)-benzodiazocine-10-carboxylic acid hexyl ester (KT 5720) and was mimicked by 8-bromo-cGMP and BAY 41-2272. In conclusion, these studies demonstrate that YC-1 stimulates the expression of HO-1 and iNOS in vascular SMCs via the PI3K and sGC-cGMP-protein kinase A pathway, respectively. The ability of YC-1 to sensitize sGC to gaseous monoxides and simultaneously stimulate their production through the induction of HO-1 and iNOS provides a potent mechanism by which the cGMP-dependent and -independent biological actions of this agent are amplified.
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PMID:YC-1 stimulates the expression of gaseous monoxide-generating enzymes in vascular smooth muscle cells. 1892 65

The proinflammatory cytokine IL-6 is released in the skin following UVB irradiation, but its potential for photoimmune modulation remains unclear. This study utilizes IL-6-deficient mice to demonstrate that IL-6 does not contribute to the normal contact hypersensitivity response, nor to its systemic suppression by UVB radiation or cis-urocanic acid. In contrast, IL-6 was required for the attenuation of UVB- or cis-urocanic acid-induced immunosuppression by sequential or concomitant UVA irradiation. The IL-6 was essential for several reactions previously established to be relevant for UVA photoimmune protection, namely the induction of heme oxygenase-1 (HO-1), the activity of its product carbon monoxide in activating guanylyl cyclase, and the consequent elevation of cutaneous cyclic guanosine monophosphate concentration. In addition, IL-6-deficient mouse skin had an elevated constitutive overexpression of HO activity, apparently not associated with photoimmune protection. This suggested that both the cutaneous level of HO activity, and the receptiveness of the HO-1 gene to stressors like UVA, normally controlled by promoter-binding repressor proteins, may also be under IL-6 control. Thus IL-6 has an important photoimmune protective function through interaction at several levels in the pathway determining the immunologically advantageous actions of UVA radiation. This may constitute a valuable endogenous antiphotocarcinogenic regulatory mechanism.
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PMID:The role of interleukin-6 in UVA protection against UVB-induced immunosuppression. 1911 May 42

The inducible nitric oxide (NO) synthase and the cytokine transforming growth factor-beta1 (TGF-beta1), both central modulators of wound healing, interact reciprocally: TGF-beta1 generally suppresses iNOS expression, while NO can induce and activate latent TGF-beta1. We have shown that chemical NO activates recombinant human latent TGF-beta1 by S-nitrosation of the latency-associated peptide (LAP), a cleaved portion of pro-TGF-beta1 that maintains TGF-beta1 in a biologically-inactive state. We hypothesized that cell-associated TGF-beta1 could be activated by NO via known NO-inducible signaling pathways (soluble guanylate cyclase [sGC] and mitogen-activated protein [MAP] kinases). Treatment of mouse RAW 264.7 macrophage-like cells with the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) led to a dose- and time-dependent increase in cell-associated active and latent TGF-beta1, as assessed by quantitative immunocytochemistry for active TGF-beta1 vs. LAP and partially validated by western blot analysis. Treatment with the sGC inhibitor 1,H-[1,2,4]oxadiazole[4,3-a]quinoxalon-1-one (ODQ) reduced both active and latent TGF-beta1 dose-dependently. SNAP, in the presence or absence of ODQ or the MAP kinase inhibitors, did not affect steady-state TGF-beta1 mRNA levels. Treatment with inhibitors specific for JNK1/2, ERK1/2, and p38 MAP kinases suppressed SNAP-induced active and latent TGF-beta1. Treatment with the cell-permeable cGMP analog 8-Br-cGMP increased both active and latent TGF-beta1. However, TGF-beta1 activation induced by 8-Br-cGMP was not blocked by MAP kinase inhibitors. Our findings suggest that NO activates latent TGF-beta1 via activation of sGC and generation of cGMP and separately via MAP kinase activation, and may shed insight into the mechanisms by which both cGMP production and MAP kinase activation enhance wound healing.
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PMID:Activation of latent transforming growth factor-beta1 by nitric oxide in macrophages: role of soluble guanylate cyclase and MAP kinases. 1961 23


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