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)

The mechanism by which nitric oxide (NO) protects from apoptosis is a matter of debate. We have shown previously that phosphorylation of tyrosine residues participates in the protection from apoptosis in insulin-producing RINm5F cells (Inorg. Chem. Commun. 3 (2000) 32). Since NO has been reported to activate the tyrosine kinase c-Src and this kinase is involved in the activation of protein kinase G (PKG) in some cell systems, we aimed at studying the contribution of c-Src and PKG systems in anti-apoptotic actions of NO in serum-deprived RINm5F cells. Here we report that exposure of serum-deprived cells to 10 microM DETA/NO results in protection from degradation of the anti-apoptotic protein Bcl-2, together with a reduction of cytochrome c release from mitochondria and caspase-3 inhibition. Studies with the inhibitors ODQ and KT-5823 revealed that these actions are dependent on both activation of guanylate cyclase and PKG. DETA/NO was also able to induce autophosphorylation and activation c-Src protein both in vivo and in vitro and active c-Src was able to induce tyrosine phosphorylation of Bcl-2 in vitro. The c-Src kinase inhibitor PP1 abrogated the actions of DETA/NO on cGMP formation, PKG activation, caspase activation, cytochrome c release from mitochondria, and Bcl-2 phosphorylation and degradation in serum-deprived cells. We thus propose that activation of c-Src is an early step in the chain of events that signal cGMP-dependent anti-apoptotic actions of NO in mitocohondria.
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PMID:Evidence for involvement of c-Src in the anti-apoptotic action of nitric oxide in serum-deprived RINm5F cells. 1158 16

The objective of this study was to elucidate the mechanisms by which nebivolol, a cardio-selective beta-adrenergic receptor antagonist, inhibits rat aortic smooth muscle cell (RASMC) proliferation. Nebivolol was compared with DETA-NO and S-nitroso-N-acetylpenicillamine (SNAP), two nitric oxide (NO) donor agents, and alpha-difluoromethylornithine (DFMO), a known inhibitor of ornithine decarboxylase (ODC). All four test agents inhibited RASMC proliferation in a concentration-dependent manner, with nebivolol being the most potent (IC(50) = 4.5 microM), whereas atenolol, another relatively selective beta(1)-blocker, was inactive. DFMO, nebivolol, and DETA-NO interfered with cell proliferation in a cell-density-dependent manner, the lower the cell density the greater the inhibition of cell proliferation. The cytostatic effects of nebivolol and DETA-NO were completely independent of cyclic GMP, as neither ODQ (cytosolic guanylyl cyclase inhibitor) nor zaprinast (cyclic GMP phosphodiesterase inhibitor) affected the antiproliferative action of nebivolol or DETA-NO. The cytostatic effects of nebivolol, SNAP, and DFMO were largely prevented by the addition of excess putrescine, but not ornithine, to cell cultures. Moreover, nebivolol caused a marked reduction in the intracellular levels of putrescine, spermidine, and spermine. Like DFMO, nebivolol and DETA-NO interfered with the G(1)-phase to S-phase cell cycle transition in RASMC. These observations confirm previous findings that DFMO and NO interfere with RASMC proliferation by inhibiting ODC and polyamine production and provide evidence that nebivolol works by the same mechanism.
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PMID:Nebivolol inhibits vascular smooth muscle cell proliferation by mechanisms involving nitric oxide but not cyclic GMP. 1222 77

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.
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PMID:Mechanisms of cytokine induced NO-mediated cardiac fibroblast apoptosis. 1238 74

Nitric oxide (NO; 1 microM) or an NO donor (500 microM diethylenetriamine-nitric oxide, DETA-NONOate) caused rapid glutamate and ATP release from cultured rat cortical astrocytes. NO-induced glutamate release was prevented by calcium chelators (EGTA or BAPTA-AM) and an inhibitor of vesicular exocytosis (botulinum neurotoxin C, BoTx-C), but not by a glutamate transport inhibitor, L-trans-pyrrolidine-2,4-dicarboxylate (t-PDC), a cyclooxygenase inhibitor (indomethacin), or an inhibitor of soluble guanylate cyclase 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), and was not induced by mitochondrial respiratory inhibitors (myxothiazol or azide). Similarly to glutamate, NO-induced ATP release was also completely blocked by BAPTA-AM and BoTx-C, suggesting again a vesicular, calcium-dependent mechanism of release. Addition of DETA-NONOate (500 microM) to fura-2-loaded astrocytes induced a rapid, transient increase in intracellular calcium levels followed by a lower, sustained level of calcium entry. The latter was blocked by gadolinium (1 microM), an inhibitor of capacitative Ca(2+) entry. Thus, NO appears to cause rapid exocytosis of vesicular glutamate and ATP from astrocytes by raising intracellular calcium levels. Astrocytes activated by lipopolysaccharide/endotoxin and interferon-gamma to express inducible NO synthase (iNOS) maintained substantially higher extracellular glutamate levels than nonactivated cells or activated cells treated with an iNOS inhibitor (1400W), but the rate of glutamate uptake by these cells was similar. This suggests that NO from inflammatory-activated astrocytes causes release of astrocytic glutamate. NO-induced release of astrocytic glutamate and ATP may be important in physiological or pathological communication between astrocytes and neurons.
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PMID:Nitric oxide induces rapid, calcium-dependent release of vesicular glutamate and ATP from cultured rat astrocytes. 1242 Mar 11

In the present study we found that mesencephalic trigeminal (Mes-V) neurons of the rat are innervated by nitrergic fibers and that nitric oxide (NO) modifies the electrophysiological properties of these cells. Mes-V neurons were surrounded by a network of fibers that contained neuronal nitric oxide synthase (nNOS); these fibers gave rise to terminal-, bouton-like structures which ended in Mes-V cells bodies. These cells, which did not display nNOS-like immunoreactivity were immunoreactive to a cGMP antibody. By performing intracellular recordings in the adult rat brain slice preparation, the effects of diethylenetriamine/NO adduct (DETA/NO) applications were examined. DETA/NO induced a depolarization that averaged 2.2 mV (range: 1-6 mV) in nine of 22 neurons. In 15 of 22 neurons (68% of the cells), there was a decrease in current threshold from 0.74 to 0.60 nA (19%; P<0.001). The excitatory effects of DETA/NO were abolished by ODQ, a blocker of soluble guanylate cyclase. Input resistance (R(in)) decreased in 80% of the cells from a mean of 24.8 to 20.6 Momega (17%; P<0.001) and the membrane time constant (tau(m)) decreased from 7.5 to 5.6 ms (25%; P<0.05). The 'sag' seen in the membrane response of these cells to current pulses was augmented during DETA/NO application. These findings indicate that there is a nitrergic innervation of Mes-V neurons and that these sensory cells are target for NO that may act on them as an excitatory neuromodulator promoting the synthesis of intracellular cGMP.
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PMID:Mesencephalic trigeminal neurons are innervated by nitric oxide synthase-containing fibers and respond to nitric oxide. 1250 60

The use of exogenous nitric oxide (NO) has been shown to alter the regulation of other endothelially derived mediators of vascular tone, such as endothelin-1 (ET-1). However, the interaction between NO and ET-1 appears to be complex and remains incompletely understood. One of the major actions of NO is the activation of soluble guanylate cyclase (sGC) with the subsequent generation of cGMP. Therefore, we undertook this study to test the hypothesis that NO regulates ET-1 production via the activation of the sGC/cGMP pathway. The results obtained indicated that the exposure of primary cultures of 4-wk-old ovine pulmonary arterial endothelial cells (4-wk PAECs) to the long-acting NO donor DETA NONOate induced both a dose- and time-dependent decrease in secreted ET-1. This decrease in ET-1 secretion occurred in the absence of changes in endothelin-converting enzyme-1 or sGC expression but in conjunction with a decrease in prepro-ET-1 mRNA. The changes in ET-1 release were inversely proportional to the cellular cGMP content. Furthermore, the NO-independent activator of sGC, YC-1, or treatment with a cGMP analog also produced significant decreases in ET-1 secretion. Conversely, pretreatment with the sGC inhibitor ODQ blocked the NO-induced decrease in ET-1. Therefore, we conclude that exposure of 4-wk PAECs to exogenous NO decreases secreted ET-1 resulting from the activation of sGC and increased cGMP generation.
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PMID:Nitric oxide decreases endothelin-1 secretion through the activation of soluble guanylate cyclase. 1469 17

NO and cGMP have antigrowth and anti-inflammatory effects on the vessel wall in response to injury. It is well established that after vascular injury proinflammatory cytokines are involved in vascular wall remodeling. The purpose of this study was to ascertain the signaling mechanisms involved in cGMP-dependent protein kinase (PKG) suppression by inflammatory cytokines in primary bovine aortic vascular smooth muscle cells (VSMC). Interleukin (IL)-Ibeta, tumor necrosis factor (TNF)-alpha, and LPS decreased the mRNA and protein levels of PKG in VSMC. IL-Ibeta, TNF-alpha, and LPS increased inducible nitric oxide synthase (iNOS) expression and cGMP production. Treatment of cells with selective inhibitors of iNOS or soluble guanylate cyclase (sGC) reversed the downregulation of PKG expression induced by cytokines and LPS. The NO donor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA NONOate) and 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1), a NO-independent sGC activator, decreased PKG mRNA and protein expression in bovine aortic VSMC. Cyclic nucleotide analogs [8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphate (CPT-cGMP) and 8-(4-chlorophenylthio)adenosine 3,5'-cyclic monophosphate (CPT-cAMP)] also suppressed PKG mRNA and protein expression. However, CPT-cAMP was more effective than CPT-cGMP in decreasing PKG mRNA levels. Selective inhibition of PKA with the Rp isomer of 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphorothioate (Rp-8p-CPT cAMPS) prevented the downregulation of PKG by LPS. In contrast, the Rp isomer of 8-(4-chlorophenylthio)guanosine 3,5'-cyclic monophosphorothioate (Rp-8p-CPT cGMPS; inhibitor of PKG) had no effect on LPS-induced inhibition of PKG mRNA and protein expression. These studies suggest that cross-activation of PKA in response to iNOS expression by inflammatory mediators downregulates PKG expression in bovine aortic VSMC.
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PMID:Downregulation of cGMP-dependent protein kinase expression by inflammatory cytokines in vascular smooth muscle cells. 1498 34

The present study tested the hypothesis that acute increases in nitric oxide (NO) exert substantial influences on gene transcription in endothelial cells (ECs) via guanylyl cyclase (GC). Human umbilical veins ECs (HUVECs) were exposed to 0.1, 1, and 10 mM of sodium nitroprusside (SNP) for 4 h and to 1 mM SNP or 250 microM of (Z)-1[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) for 2, 4, 8, and 24 h. Also, cells were exposed to DETA-NONOate in the presence and absence of the GC inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 10 microM) for 4 h. RNA was isolated, reverse transcribed, Cy3 and Cy5 labeled, and analyzed using cDNA microarrays. Increasing doses of SNP predominantly depressed gene expression in HUVECs. Gene function was related to growth, adhesion, and cell structure. DETA-NONOate evoked a wave of expression changes (maximum at 4 h), with a remarkable downregulation of the transcription factors MSX1, RELB, and Egr-1. Both SNP- and DETA-NONOate-induced gene expression had faded after 24 h, despite continued elevation of cGMP in the medium. Coadministration of ODQ decreased many, but not all, of the transcriptional responses to DETA-NONOate. NO pronouncedly depressed EC gene expression, in particular of transcription factors. The observation that many, but not all, transcriptional changes induced by NO could be inhibited by inhibition of GC indicates the presence of GC-independent NO actions on gene expression. Thus EC gene expression responds to NO; however, the transcriptional response fades during prolonged exposure. This could allow the EC to respond to increased shear, without vigorous changes in gene expression.
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PMID:Nitric oxide donor induces temporal and dose-dependent reduction of gene expression in human endothelial cells. 1524 32

The hypothesis that the NO/cGMP pathway modulates PMN adhesion to human brain microvessel endothelial cells (HBMEC) was examined. Human PMN were incubated with resting or TNF-alpha-treated endothelial monolayers, and adhesion was quantified by light microscopy. TNF-alpha upregulated PMN adhesion in a time-dependent manner. Treatment of HBMEC with the NO donors SNP and DETA NONOate for 4 or 24 h decreased PMN adhesion. This was completely reversed by the guanylyl cyclase inhibitor ODQ, while addition of a cGMP agonist (8-Br-cGMP) decreased PMN adhesion. NO donors did not affect the levels of E-selectin or ICAM-1 in HBMEC. However, pre-treatment of PMN with NO donors or 8-Br-cGMP decreased their adhesion to recombinant E-selectin and ICAM-1, suggesting an effect of NO on PMN. These findings indicate that NO modulates PMN-HBMEC interactions through cGMP and decreases the binding of PMN to the adhesion molecules E-selectin and ICAM-1.
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PMID:Nitric oxide regulates interactions of PMN with human brain microvessel endothelial cells. 1535 13

1. Prednisolone, a potent anti-inflammatory drug, has proved ineffective in treating acute respiratory distress syndrome (ARDS). ARDS is associated with superoxide (O(2)(*-)) generation, which negates nitric oxide (NO). NO also downregulates NADPH oxidase and inhibits O(2)(*-) formation. A possible reason for the lack of effect of prednisolone may due to an inhibition of eNOS expression. In order to test this proposal, the effect of prednisolone on O(2)(*-) formation and the expression of gp91(phox) (catalytic subunit of NADPH oxidase) and eNOS in pig pulmonary artery (PA) segments and PA endothelial cells (PAECs) and PA vascular smooth muscle cells (PAVSMCs) was investigated. 2. PA segments and cells were incubated with prednisolone and tumour necrosis factor-alpha (TNF-alpha) for 16 h. O(2)(*-) formation was measured spectrophometrically and gp91(phox) and eNOS expression by Western blotting. The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride, the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ) and the stable cGMP analogues, 8-bromo cGMP and 8-(4-chlorophenylthio)-cGMP (8-pCPT-cGMP). NO release was studied using a fluorescence assay and O(2)(*-)-NO interactions with a nitrite/nitrate assay. 3. Prednisolone elicited significant increase in O(2)(*-) formation in intact PA segments and PAECs, but not PAVSMCs, in a concentration-dependent manner. In endothelium-denuded segments, prednisolone slightly enhanced O(2)(*-) release. TNF-alpha further increased prednisolone-enhanced O(2)(*-) formation in intact PA segments and PAECs. NADPH oxidase inhibitor, apocynin, inhibited O(2)(*-) formation. Increased O(2)(*-) release and gp91(phox) expression in PAECs elicited by prednisolone was blocked by SIN-1 (3-morpholinosydnonimine hydrochloride), DETA-NONOate, 8-pCPT-cGMP and 8-bromo cGMP. The effects of SIN-1 on gp91(phox) expression were reversed by ODQ. Finally, eNOS protein expression was significantly reduced by prednisolone. 4. Prednisolone increases O(2)(*-) in porcine PAECs through a downregulation of endogenous eNOS expression. Since the NO-cGMP axis inhibits gp91(phox) expression, the resultant decrease in endogenous NO formation then augments NADPH oxidase activity, which in turn results in increased O(2)(*-) formation. Since O(2)(*-) promotes inflammation, this mechanism may explain why prednisolone is ineffective in treating ARDS. Therapeutically, the coadministration of an NO donor may render prednisolone more effective in treating ARDS.
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PMID:Prednisolone augments superoxide formation in porcine pulmonary artery endothelial cells through differential effects on the expression of nitric oxide synthase and NADPH oxidase. 1585 33


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