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)

PPCM (previously designated sulfuric acid-modified mandelic acid [SAMMA]) is a contraceptive microbicide in preclinical development. Its contraceptive activity is attributable in part to its ability to promote premature acrosomal loss. Prior studies showed that PPCM-induced human acrosomal loss (PAL) is Ca(2+)-dependent. This study was carried out to determine transduction elements downstream from Ca(2+) entry. PAL is inhibited by inhibitors selective for endothelial-type nitric oxide synthase. PAL is completely inhibited by 0.1 microM ODQ (soluble guanylate cyclase inhibitor). PAL is inhibited by protein kinase G inhibitors with selectivity for the type II isotype. Several inhibitors of the nitric oxide/cyclic guanosine monophosphate (cGMP)/protein kinase G pathway induce Ca(2+)-dependent acrosomal loss when added alone. These responses are inhibited by nifedipine, a blocker of Ca(v1.x) voltage-dependent channels. Acrosomal loss induced by the nitric oxide donor SNAP (SNAL) does not require added Ca(2+). Sperm production of nitric oxide is increased by PPCM, an effect inhibited by nitro-L-arginine (nitric oxide synthase inhibitor). Although inhibited by ODQ, SNAL and acrosomal loss induced by other nitric oxide donors are unaffected by KT5823 (protein kinase G inhibitor). Unlike PAL, SNAL is partially inhibited by KT5720 (protein kinase A inhibitor) and genistein (protein tyrosine kinase inhibitor). Acrosomal loss response to PPCM and SNAP added in combination suggests that these agents act by independent mechanisms. A PPCM derivative was synthesized, in which a nitric oxide donor was esterified to PPCM (NOSPPA-23). NOSPPA-23 induces acrosomal loss with or without added Ca(2+). The ED(50) of NOSPPA-23 (4.8 nM) in the presence of Ca(2+) is 35-fold less than that of PPCM. These findings suggest the following: 1) elements responsible for PAL include endothelial nitric oxide synthase, soluble guanylate cyclase, and type II protein kinase G; 2) the resting state of the nitric oxide/cGMP/protein kinase G pathway is a determinant of acrosomal status; 3) PPCM and nitric oxide donors induce acrosomal loss via nitric oxide, but through independent pathways; and 4) covalent attachment of a nitric oxide donor to PPCM provides synergistic efficacy as a stimulus of acrosomal loss. Further studies with this novel prototype as an improved contraceptive microbicide are warranted.
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PMID:Nitric oxide-dependent human acrosomal loss induced by PPCM (SAMMA) and by nitric oxide donors occurs by independent pathways: basis for synthesis of an improved contraceptive microbicide. 1897 24

Microglia migrate rapidly to lesions in the central nervous system (CNS), presumably in response to chemoattractants including ATP released directly or indirectly by the injury. Previous work on the leech has shown that nitric oxide (NO), generated at the lesion, is both a stop signal for microglia at the lesion and crucial for their directed migration from hundreds of micrometers away within the nerve cord, perhaps mediated by a soluble guanylate cyclase (sGC). In this study, application of 100 microM ATP caused maximal movement of microglia in leech nerve cords. The nucleotides ADP, UTP, and the nonhydrolyzable ATP analog AMP-PNP (adenyl-5'-yl imidodiphosphate) also caused movement, whereas AMP, cAMP, and adenosine were without effect. Both movement in ATP and migration after injury were slowed by 50 microM reactive blue 2 (RB2), an antagonist of purinergic receptors, without influencing the direction of movement. This contrasted with the effect of the NO scavenger cPTIO (2-(4-carboxyphenyl)-4,4,5,5-teramethylimidazoline-oxyl-3-oxide), which misdirected movement when applied at 1 mM. The cPTIO reduced cGMP immunoreactivity without changing the immunoreactivity of eNOS (endothelial nitric oxide synthase), which accompanies increased NOS activity after nerve cord injury, consistent with involvement of sGC. Moreover, the sGC-specific inhibitor LY83583 applied at 50 microM had a similar effect, in agreement with previous results with methylene blue. Taken together, the experiments support the hypothesis that ATP released directly or indirectly by injury activates microglia to move, whereas NO that activates sGC directs migration of microglia to CNS lesions.
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PMID:ATP and NO dually control migration of microglia to nerve lesions. 1902 30

Pleiotrophin (PTN) is a secreted growth factor involved in angiogenesis and tumor growth. We have recently shown that low concentrations of hydrogen peroxide (HP) stimulate PTN expression, through activation of the transcription factor AP-1. In the present work, we studied the possible involvement of endothelial nitric oxide synthase (eNOS) and the role of nitric oxide (NO) in the regulation of PTN expression, as well as involvement of the latter in the NO-induced human endothelial and prostate cancer cell migration. Inhibition of eNOS or the downstream effector soluble guanylate cyclase (sGC) completely suppressed HP-induced AP-1 activities that lead to PTN expression and cell migration. The NO donor sodium nitroprusside (SNP) through activation of sGC significantly and concentration-dependently increased expression of PTN, through transcriptional activation of the corresponding gene. Moreover, SNP had no effect on the migration of stably transfected prostate cancer cells that do not express PTN and knockdown of PTN receptor protein tyrosine phosphatase beta/zeta (RPTPbeta/zeta) completely abolished SNP-induced cell migration. NO added exogenously or produced endogenously by low concentrations of HP through stimulation of sGC activates extracellular signal-regulated kinase[1/2] (ERK[1/2]) and leads to PTN expression and cell migration. On the other hand, p38, which also intervenes in the up-regulation of PTN expression by low concentrations of HP, seems to act upstream of eNOS and does not intervene in the SNP-induced PTN expression and cell migration. The above data suggest that PTN through its receptor RPTPbeta/zeta is a mediator of the stimulatory effects of eNOS/NO on human endothelial and prostate cancer cell migration.
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PMID:Nitric oxide stimulates migration of human endothelial and prostate cancer cells through up-regulation of pleiotrophin expression and its receptor protein tyrosine phosphatase beta/zeta. 1905 21

As a gatekeeper of leukocyte trafficking the vasculature fulfills an essential immune function. We have recently shown that paracellular transendothelial lymphocyte migration is controlled by intercellular adhesion molecule 1 (ICAM-1)-mediated vascular endothelial cadherin (VEC) phosphorylation [Turowski et al., J. Cell Sci. 121, 29-37 (2008)]. Here we show that endothelial nitric oxide synthase (eNOS) is a critical regulator of this pathway. ICAM-1 stimulated eNOS by a mechanism that was clearly distinct from that utilized by insulin. In particular, phosphorylation of eNOS on S1177 in response to ICAM-1 activation was regulated by src family protein kinase, rho GTPase, Ca(2+), CaMKK, and AMPK, but not Akt/PI3K. Functional neutralization of any component of this pathway or its downstream effector guanylyl cyclase significantly reduced lymphocyte diapedesis across the endothelial monolayer. In turn, activation of NO signaling promoted lymphocyte transmigration. The eNOS signaling pathway was required for T-cell transmigration across primary rat and human microvascular endothelial cells and also when shear flow was applied, suggesting that this pathway is ubiquitously used. These data reveal a novel and essential role of eNOS in basic immune function and provide a key link in the molecular network governing endothelial cell compliance to diapedesis.
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PMID:ICAM-1-mediated endothelial nitric oxide synthase activation via calcium and AMP-activated protein kinase is required for transendothelial lymphocyte migration. 1907 85

The aim of this study was to identify and elucidate the vasorelaxant activity of echinacoside, a phenylethanoid glycoside isolated from the medicinal herb Cistanche tubulosa, and its possible underlying mechanism on isolated rat thoracic aortic rings pre-contracted with phenylephrine (PE, 1 microM) and KCl (60 mM). Echinacoside (30-300 microM) exhibited an acute relaxation in endothelium-intact rings in a concentration-dependent manner, while this relaxation was significantly inhibited in endothelium-denuded condition and in the presence of the endothelial nitric oxide synthase (eNOS) inhibitor, N(W)-nitro-L-arginine methyl ester (L-NNA, 100 microM), an unselective soluble guanylate cyclase blocker, methylene blue (10 microM), the selective sGC inhibitor 1 H-[1, 2, 4]oxadiazolo[4,3- A]quinoxalin-1-one (ODQ, 1 microM); in addition, atropine (1 microM), a selective muscarinic receptor antagonist, partially affected the relaxation. However, the cyclooxygenase inhibitor indomethacin (5 microM) had no influence on the action. Echinacoside enhanced the cyclic guanosine monophosphate (cGMP) production in aortic rings contracted with PE. These results indicate for the first time that echinacoside mediates the endothelium-dependent vasodilator action in rat thoracic aortic rings through nitric oxide (NO)-cGMP pathway.
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PMID:Echinacoside elicits endothelium-dependent relaxation in rat aortic rings via an NO-cGMP pathway. 1946 74

We hypothesized that targeted mutation of the endothelial nitric oxide synthase (eNOS) gene would reduce Akt-related signaling events in skeletal muscle cells, compared to wild type (WT) controls. Results show that slow myosin heavy chain (type I/beta) expression and the abundance of slow-twitch fibers are reduced in plantaris muscle of eNOS(-/-) mice, compared to WT. Further, basal phosphorylation of Akt (p-Akt (Ser-473)/total Akt) and GSK-3beta (GSK-3beta (Ser-9)/total GSK-3beta) are reduced 60-70% in primary myotubes from eNOS(-/-) mice. Treatment with the calcium ionophore, A23187 (0.4 microM, 1 h), increased phosphorylation of Akt and GSK-3beta by approximately 2-fold (P<0.05) in myotubes from WT mice, but had no effect on phosphorylation of these proteins in eNOS(-/-) myotubes. Additionally, A23187 treatment failed to induce nuclear translocation of the transcription factor, NFATc1, in eNOS(-/-) myotubes. Treatment with the nitric oxide donor, propylamine propylamine NONOate (PAPA-NO; 1 microM for 1 h) increased Akt and GSK-3beta phosphorylation, and induced NFATc1 nuclear translocation in WT and eNOS(-/-) myotubes, and eliminated differences from WT in the NOS knockout cultures. Parallel experiments in C2C12 myotubes found that Akt phosphorylation induced by NO or the guanylate cyclase activator, YC-1, is prevented by co-treatment with either a guanylate cyclase or PI3K inhibitor (10 microM ODQ or 25 microM LY2904002, respectively). These data suggest that eNOS activity is necessary for calcium-induced activation of the Akt pathway, and that nitric oxide is sufficient to elevate Akt activity in primary myotubes. NO appears to influence Akt signaling through a cGMP, PI3K-dependent pathway.
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PMID:Endothelial nitric oxide synthase is involved in calcium-induced Akt signaling in mouse skeletal muscle. 1968 97

Radial artery (RA) vasospasm remains a potential cause of early graft failure after coronary artery bypass graft surgery, despite pretreatment with alpha-adrenergic or calcium channel blockers. Our aim was to investigate the mechanism of the vasorelaxant effects of Rho-kinase inhibitors (Y-27632 and fasudil) on the human RA. Segments were obtained from 30 patients undergoing coronary artery bypass graft and were divided into 3-4 mm vascular rings. The rings were stimulated with 10(-5) mol/L phenylephrine (PE) by using the isolated tissue bath technique and were relaxed with 10(-6) mol/L acetylcholine. Relaxation responses were recorded for Y-27632 (10(-9)-10(-4) mol/L), fasudil (10(-9)-10(-4) mol/L), and sodium nitroprusside (SNP) (10(-9)-10(-5) mol/L). Y-27632 and fasudil relaxation responses were repeated in either N(G)-nitro-L-arginine (L-NNA), which is a specific endothelial nitric oxide synthase inhibitor, or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which is a guanylate cyclase inhibitor. SNP relaxation responses were repeated in 10(-8) mol/L Y-27632 and 10(-8) mol/L fasudil. Y-27632 and fasudil caused concentration-dependent vasorelaxation in RA rings precontracted with PE, and maximal relaxation (100%) was recorded at the highest concentration used (10(-4) mol/L). The vasorelaxant effects of Y-27632 and fasudil were significantly reduced in the presence of L-NNA and ODQ, and the pD2 values of Y-27632 and fasudil were not changed. The vasorelaxant effects of SNP were significantly increased in the presence of Y-27632 and fasudil, and the pD(2) values of SNP were not changed. These findings indicate that Y-27632 and fasudil caused concentration-dependent vasorelaxation in the RA rings. Because this effect was decreased in a dose-dependent manner by L-NNA and ODQ, the relaxant effects of Y-27632 and fasudil could be due to stimulation by nitric oxide that is being released. Rho-kinase inhibitors may have an important role in preventing vasospasm in arterial grafts used for coronary artery surgery.
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PMID:Rho-kinase inhibitors Y-27632 and fasudil prevent agonist-induced vasospasm in human radial artery. 1976 83

Nitric oxide (NO), synthesized by endothelial nitric oxide synthase (eNOS), exerts control over vascular function via two distinct mechanisms, the activation of soluble guanylate cyclase (sGC)/cGMP-dependent signaling or through S-nitrosylation of proteins with reactive thiols (S-nitrosylation). Previous studies in cultured endothelial cells revealed that eNOS targeted to the plasma membrane (PM) releases greater amounts of NO compared with Golgi tethered eNOS. However, the significance of eNOS localization to sGC-dependent or -independent signaling is not known. Here we show that PM-targeted eNOS, when expressed in human aortic endothelial cells (HAEC) and isolated blood vessels, increases sGC/cGMP signaling to a greater extent than Golgi-localized eNOS. The ability of local NO production to influence sGC-independent mechanisms was also tested by monitoring the secretion of Von Willebrand factor (vWF), which is tonically inhibited by the S-nitrosylation of N-ethylmaleimide sensitive factor (NSF). In eNOS "knockdown" HAECs, vWF secretion was attenuated to a greater degree by PM eNOS compared with a Golgi-restricted eNOS. Moreover, the PM-targeted eNOS induced greater S-nitrosylation of NSF vs. Golgi eNOS. To distinguish between the amount of NO generated and the intracellular location of synthesis, we expressed Golgi and PM-targeted calcium-insensitive forms of eNOS in HAEC. These constructs, which generate equal amounts of NO regardless of location, produced equivalent increases in cGMP in bioassays and equal inhibition of vWF secretion. We conclude that the greater functional effects of PM eNOS are due to the increased amount of NO produced rather than effects derived from the local synthesis of NO.
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PMID:Role of local production of endothelium-derived nitric oxide on cGMP signaling and S-nitrosylation. 1985 60

Monocrotaline (MCT)-induces progressive disruption of endothelial cell membrane and caveolin-1 leading to pulmonary arterial hypertension (PAH). Treatment instituted early rescues caveolin-1 and attenuates PAH. To test the hypothesis that the poor response to therapy in established PAH is due to progressive deregulation of multiple signaling pathways, the authors investigated time-dependent changes in the expression of caveolin-1, gp130, PY-STAT3, Bcl-xL, and the molecules involved in NO signaling pathway (endothelial nitric oxide synthase [eNOS], heat sock protein 90 [HSP90], Akt, soluble guanylate cyclase [sGC] alpha1 and beta1 subunits). PAH and right ventricular hypertrophy (RVH) were observed at 2 and 3 weeks. Progressive loss of endothelial caveolin-1 and sGC (alpha1, beta1), PY-STAT3 activation, and Bcl-xL expression were observed at 1 to 3 weeks post-MCT. The expression of gp130 increased at 48 hours and 1 week, with a subsequent loss at 2 and 3 weeks. The expression of eNOS increased at 48 hours and 1 week post-MCT, with a significant loss at 3 weeks. The expression of HSP90 and Akt decreased at 2 and 3 weeks post-MCT concomitant with PAH. Thus, MCT induces progressive loss of membrane and cytosolic proteins, resulting in the activation of proliferative and antiapoptotic factors, and deregulation of NO signaling leading to PAH. An attractive therapeutic approach to treat PAH may be an attempt to rescue endothelial cell membrane integrity.
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PMID:Progressive endothelial cell damage in an inflammatory model of pulmonary hypertension. 2012 82

The benzoquinone derivative embelin is a multifunctional drug that not only induces apoptosis by inhibiting XIAP, the X chromosome-linked inhibitor of apoptosis protein, but also blocks nuclear factor-kappaB signaling pathways, thereby leading to down-regulation of a variety of gene products involved in tumor cell survival, proliferation, invasion, angiogenesis, and inflammation. Here, we report that embelin activates and modulates l-arginine/nitric oxide/cyclic GMP signaling in cultured endothelial cells. Embelin elicited a rapid increase of intracellular free Ca(2+), leading to activation of endothelial nitric oxide synthase (eNOS) and NO-induced cGMP accumulation. While the cGMP response was comparable to that caused by other Ca(2+)-mobilizing agents, the stimulatory effect of embelin on l-citrulline formation (approximately 4-fold) was substantially lower than that observed upon activation of eNOS with the Ca(2+) ionophore A23187 (approximately 18-fold), the receptor agonist ATP (approximately 16-fold) or the sarco-endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin (approximately 14-fold). The apparent discrepancy between NO/cGMP and l-citrulline formation in embelin-treated cells was not due to enhanced metabolism and/or efflux of l-citrulline, increased NO bioavailability, inhibition of cGMP hydrolysis, sensitization of soluble guanylate cyclase (sGC) to NO, or enhanced formation of a sGC/eNOS complex. Our puzzling observations suggest that embelin improves coupling of endothelial NO synthesis to sGC activation through mobilization of an as yet unrecognized signaling pathway.
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PMID:Activation of endothelial nitric oxide synthase by the pro-apoptotic drug embelin: Striking discrepancy between nitric oxide-mediated cyclic GMP accumulation and L-citrulline formation. 2014 27


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