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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) has been proposed to exert neuroprotective actions against oxidative damage acting directly as an antioxidant; in addition, it has also been suggested that NO might be cytoprotective by increasing cyclic GMP concentrations via activation of soluble guanylate cyclase. In this context, we have previously shown that cyclic GMP elevations confer cytoprotection against the neurotoxicity induced by SIN-1 in the presence of superoxide dismutase, conditions in which cell death seems to be a consequence of hydrogen peroxide (H2O2) formation. We have now found that H2O2 (20-100 microM) causes neurotoxicity in 1-week-old rat cortical neurones and that this effect is inhibited by the NO donor DETA-NONOate (1-10 microM). We have also found that 1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylate cyclase, reverses the effect induced by DETA-NONOate, and that this action of ODQ is mimicked by 8-(4-chlorophenylthio)guanosine-3',5'-monophosphorothioate (Rp-8-pCPT-cGMPS), an inhibitor of cyclic GMP-dependent protein kinase, suggesting that the pathway affording protection involves activation of this kinase by cyclic GMP elevations. Simultaneously, ODQ inhibits the elevation of cyclic GMP concentrations induced by DETA-NONOate (1-3 microM) in cortical cells. Finally, we have also shown that the cyclic GMP mimetic, 8-bromoguanosine 3':5'-cyclic monophosphate (8-Br-cyclic GMP) inhibits the neurotoxicity induced by H2O2 (30-40 microM). Taken together, these data demonstrate that NO-induced cyclic GMP elevations confer cytoprotection against H2O2-induced neuronal cell death.
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PMID:Neuroprotective effects of DETA-NONOate, a nitric oxide donor, on hydrogen peroxide-induced neurotoxicity in cortical neurones. 1047 Oct 84

The bioactivity of endothelium-derived nitric oxide (NO) reflects its rates of production and of inactivation by superoxide (O(2)(*-)), a reactive species dismutated by extracellular superoxide dismutase (ecSOD). We have now examined the complementary hypothesis, namely that NO modulates ecSOD expression. The NO donor DETA-NO increased ecSOD expression in a time- and dose-dependent manner in human aortic smooth muscle cells. This effect was prevented by the guanylate cyclase inhibitor ODQ and by the protein kinase G (PKG) inhibitor Rp-8-CPT-cGMP. Expression of ecSOD was also increased by 8-bromo-cGMP, but not by 8-bromo-cAMP. Interestingly, the effect of NO on ecSOD expression was prevented by inhibition of the MAP kinase p38 but not of the MAP kinase kinase p42/44, suggesting that NO modulates ecSOD expression via cGMP/PKG and p38MAP kinase-dependent pathways, but not through p42/44MAP kinase. In aortas from mice lacking the endothelial nitric oxide synthase (eNOS), ecSOD was reduced more than twofold compared to controls. Treadmill exercise training increased eNOS and ecSOD expression in wild-type mice but had no effect on ecSOD expression in mice lacking eNOS, suggesting that this effect of exercise is meditated by endothelium-derived NO. Upregulation of ecSOD expression by NO may represent an important feed-forward mechanism whereby endothelial NO stimulates ecSOD expression in adjacent smooth muscle cells, thus preventing O(2)(*-)-mediated degradation of NO as it traverses between the two cell types.
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PMID:Regulation of the vascular extracellular superoxide dismutase by nitric oxide and exercise training. 1084 22

Contraction of three-dimensional collagen gels is a model of the contraction that characterizes normal healing and remodeling after injury. In the current study, we evaluated the hypothesis that a number of inflammatory factors, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and interferon (IFN)-gamma, modulate this process by induction of prostaglandin (PG) E(2) and nitric oxide (NO) production and that these secondary mediators function in an autocrine or paracrine manner to modulate contraction. Human fetal lung fibroblasts (HFL) were cultured in type I collagen gels and floated in medium containing TNF-alpha, IL-1 beta, or IFN-gamma alone or in combination (cytomix). All cytokines inhibited the contraction significantly. The potency order was IL-1 beta, TNF-alpha, IFN-gamma. The cytomix was no more potent than was IL-1 beta alone. PGE(2) production was increased by TNF-alpha (5.0 versus 0.16 ng/ml, P < 0.01), IL-1 beta (5.3 versus 0.16 ng/ml, P < 0.01), and cytomix (5.9 versus 0.16 ng/ml, P < 0.01), and was completely inhibited by indomethacin. Indomethacin (P < 0.05) and L-NG-monomethyl arginine citrate (L-NMMA) (P < 0.05) alone both partially attenuated the inhibition of contraction caused by cytokines alone or by cytomix. Indomethacin and L-NMMA together attenuated inhibition more than either alone (P < 0.05). Exogenous PGE(2) and exogenous NO donors (DETA nononate and 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride) inhibited the contraction significantly. The protein kinase A inhibitor KT5270 and the protein kinase G inhibitor Rp-pCPT-cGMPS attenuated the inhibition induced by PGE(2) and NO, respectively. In summary, PGE(2) and NO appear to function in parallel as autocrine/paracrine mediators of cytokine-driven fibroblast inhibition of the contraction of collagen gels and may contribute to remodeling during repair and inflammation in lung disorders.
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PMID:Cytokine inhibition of fibroblast-induced gel contraction is mediated by PGE(2) and NO acting through separate parallel pathways. 1150 36

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 purpose of this study was to investigate the role of endothelial nitric-oxide synthase (eNOS), cAMP, and p38 MAPK in tumor necrosis factor-alpha (TNF-alpha) expression induced by lipopolysaccharide (LPS). LPS dose- and time-dependently induced phosphorylation of p38 MAPK and TNF-alpha expression in neonatal mouse cardiomyocytes. TNF-alpha expression was preceded by p38 MAPK phosphorylation, and selective inhibition of p38 MAPK abrogated LPS-induced TNF-alpha expression. Deficiency in eNOS decreased basal and LPS-stimulated TNF-alpha expression in cardiomyocytes. NOS inhibitor l-NAME attenuated LPS-induced p38 MAPK phosphorylation and TNF-alpha production in wild-type cardiomyocytes, whereas NO donor 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (DETA-NO) (2 microm) or overexpression of eNOS by adenoviral gene transfer restored the response of eNOS(-/-) cardiomyocytes to LPS. These effects of NO were mediated through cAMP-dependent pathway based on the following facts. First, deficiency in eNOS decreased basal levels of intracellular cAMP, and DETA-NO elevated intracellular cAMP levels in eNOS(-/-) cardiomyocytes. Second, a cAMP analogue 8-Br-cAMP mimicked the effect of NO in eNOS(-/-) cardiomyocytes. Third, either inhibition of cAMP or cAMP-dependent protein kinase attenuated LPS-stimulated p38 MAPK phosphorylation and TNF-alpha production in wild-type cardiomyocytes. In conclusion, eNOS enhances LPS-stimulated TNF-alpha expression in cardiomyocytes. Activation of p38 MAPK is essential in LPS-stimulated TNF-alpha expression. Moreover, the effects of NO on LPS-stimulated TNF-alpha expression are mediated through cAMP/cAMP-dependent protein kinase-dependent p38 MAPK pathway in neonatal cardiomyocytes.
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PMID:Endothelial nitric-oxide synthase enhances lipopolysaccharide-stimulated tumor necrosis factor-alpha expression via cAMP-mediated p38 MAPK pathway in cardiomyocytes. 1250 17

The addition of atrial natriuretic peptide (ANP) to isolated human adipocytes in primary culture from very obese individuals resulted in an inhibition of leptin release after a 24- or 48-hr incubation. There was also an inhibition of leptin release by isoproterenol (ISO) that was partially reversed by insulin, whereas the inhibition due to ANP was unaffected. Similar results were seen with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H-89), which is a cell-permeable inhibitor of protein kinase A. H-89 markedly reduced the effects of ISO on both lipolysis and leptin release without affecting the stimulation of lipolysis or the inhibition of leptin release due to ANP. Inhibition of endogenous nitric oxide formation using N(omega)-nitro-L-arginine resulted in a 20% increase in leptin release over 48 hr, which suggests that the nitric oxide/cyclic GMP pathway might play a small role in the regulation of endogenous leptin release. Similarly, the addition of the nitric oxide donor (Z)-1-[2-aminoethyl)-N-(2-aminoethyl)diazen-1-ium-1,2-diolate (DETA NONOate) at 0.1 or 1 microM to explants of human adipose tissue enhanced lipolysis by 29%. Our data demonstrate that the lipolytic effect of ANP is probably secondary to stimulation of cyclic GMP accumulation in human adipocytes, and this is accompanied by an inhibition of leptin release.
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PMID:Inhibition of leptin release by atrial natriuretic peptide (ANP) in human adipocytes. 1278 40

Continuous exposure to nitrovasodilators and nitric oxide induces tolerance to their vasodilator effects in vascular smooth muscle. This study was done to determine the role of cGMP-dependent protein kinase (PKG) in the development of tolerance to nitric oxide. Isolated fourth-generation pulmonary veins of newborn lambs were studied. Incubation of veins for 20 h with DETA NONOate (DETA NO; a stable nitric oxide donor) significantly reduced their relaxation response to the nitric oxide donor and to beta-phenyl-1,N2-etheno-8-bromo-cGMP (8-Br-PET-cGMP, a cell-permeable cGMP analog). Incubation with DETA NO significantly reduced PKG activity and protein and mRNA levels in the vessels. These effects were prevented by 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (an inhibitor of soluble guanylyl cyclase) and Rp-8-Br-PET-cGMPS (an inhibitor of PKG). A decrease in PKG protein and mRNA levels was also observed after continuous exposure to cGMP analogs. The PKG inhibitor abrogated these effects. The decrease in cGMP-mediated relaxation and in PKG activity caused by continuous exposure to DETA NO was not affected by KT-5720, an inhibitor of cAMP-dependent protein kinase. Prolonged exposure to 8-Br-cAMP (a cell-permeable cAMP analog) did not affect PKG protein level in the veins. These results suggest that continuous exposure to nitric oxide or cGMP downregulates PKG by a PKG-dependent mechanism. Such a negative feedback mechanism may contribute to the development of tolerance to nitric oxide in pulmonary veins of newborn lambs.
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PMID:Role of cGMP-dependent protein kinase in development of tolerance to nitric oxide in pulmonary veins of newborn lambs. 1466 Apr 86

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 endothelial cells (EC) of the microvasculature in the brain form the anatomical basis of the blood-brain barrier (BBB). In the present study, the effects of agents that modify the permeability of a well-established in vitro model of the human BBB were studied. The monolayers formed by confluent human brain microvessel endothelial cell (HBMEC) cultures are impermeable to the macromolecule tracer horseradish peroxidase (HRP) and have high electrical resistance. Exposure of HBMEC to various cytokines including TNF-alpha, IL-1beta, interferon gamma (IFN-gamma), or lipopolysaccharide (LPS) decreased transendothelial electrical resistance (TEER) mainly by increasing the permeability of the tight junctions. Primary cultures of HBMEC express endothelial nitric oxide synthase (eNOS) and produce low levels of NO. Treatment with the NO donors sodium nitroprusside (SNP) and DETA NONOate or the cGMP agonist 8-Br-cGMP significantly increased monolayer resistance. Conversely, inhibition of soluble guanylyl cyclase with ODQ rapidly decreased the resistance, and pretreatment of HBMEC with Rp-8-CPT-cGMPS, an inhibitor of cGMP-dependent protein kinase, partially prevented the 8-Br-cGMP-induced increase in resistance. Furthermore, NO donors and 8-Br-cGMP could also reverse the increased permeability of the monolayers induced by IL-1beta, IFN-gamma, and LPS. These results indicate that NO can decrease the permeability of the human BBB through a mechanism at least partly dependent on cGMP production and cGMP-dependent protein kinase activation.
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PMID:Cytokines, nitric oxide, and cGMP modulate the permeability of an in vitro model of the human blood-brain barrier. 1553 Aug 83

Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O(2)(*-)) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP-mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO-mediated inhibition of NADPH oxidase. Therefore, the effect of sildenafil citrate and NO-donating sildenafil (NCX 911) on O(2)(*-) formation and gp91(phox) (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs). PAECs were incubated with 10 nM TXA(2) analogue, 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prostaglandin F(2alpha) (U46619) (+/-sildenafil or NCX 911), for 16 h and O(2)(*-) formation measured spectrophometrically and gp91(phox) using Western blotting. The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN-1), the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ), and the protein kinase G inhibitor, 8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS). NO release was studied using a fluorescence assay and O(2)(*-)-NO interactions by measuring nitrites. After a 16-h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration-dependent inhibition of O(2)(*-) formation and gp91(phox) expression, NCX 911 being more potent (IC(50); 0.26 nM) than sildenafil citrate (IC(50); 1.85 nM). These inhibitory effects were reversed by 1 microM ODQ and 10 microM Rp-8-Br-cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell-free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 muM SIN-1 and blocked partially by the eNOS inhibitor 10 microM N(5)-(1-iminoethyl)-ornithine (L-NIO). Acutely, sildenafil and NCX 911 also inhibited O(2)(*-) formation, again blocked by 1 microM ODQ. NCX 911 reacted with O(2)(*-) generated by xanthine oxidase, an effect that was inhibited by superoxide dismutase (500 U ml(-1)). Since O(2)(*-) formation plays contributory role in ARDS, both sildenafil citrate and NCX 911 may be indicated for treating ARDS through suppression of NADPH oxidase expression and therefore of O(2)(*-) formation and preservation of NO bioavailability.
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PMID:Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91phox expression in porcine pulmonary artery endothelial cells. 1598 Aug 72


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