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)

Tetrahydrobiopterin (BH4) biosynthetic pathways are stimulated under inflammatory conditions. The newly synthesized BH4 serves as a cofactor for optimal activity of inducible nitric oxide synthase (NOS2). In human mesangial cells (HMC), BH4 is also a limiting factor for NOS2 expression. In this study we show that BH4 availability can also play a modulatory role in the expression of cyclooxygenase 2 (COX-2) in HMC. Supplementing HMC with the BH4 donor sepiapterin potentiated IL-1beta/TNF-alpha-induced COX-2 expression by approximately 2-fold. This effect was abolished by methotrexate. In contrast, the NOS inhibitor L-NAME and the soluble guanylate cyclase inhibitor ODQ did not block sepiapterin amplification of COX-2 expression. Moreover, sepiapterin was found to modulate the tyrosine phosphorylation of several cellular substrates, an early event which occurred well before the induction of NOS2 could be evidenced. These findings suggest a role for BH4 in the modulation of mesangial cell responses to pro-inflammatory stimuli.
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PMID:Tetrahydrobiopterin modulates cyclooxygenase-2 expression in human mesangial cells. 940 25

We hypothesized that nitric oxide (NO) production by the fetal ductus arteriosus is limited because of low fetal PO2, but that at neonatal PO2, NO might be an important regulator of ductus arteriosus tone. We exposed isolated rings of fetal lamb ductus arteriosus to elevated PO2. L-NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), and methylene blue and 6-anilino-5,8-quinolinedione (LY83583), inhibitors of guanylate cyclase, produced constriction of the ductus arteriosus. When ductus arteriosus rings were exposed to low PO2, L-NAME had no effect, and methylene blue and LY83583 had only a small effect on ductus arteriosus tone. Sodium nitroprusside and calcium ionophore A23187 relaxed ductus arteriosus rings more than aortic rings, and relaxed ductus arteriosus rings from immature fetuses more than those from late gestation fetuses. In contrast, ductus arteriosus rings from both early and late gestation were equally sensitive to 8-bromo-cGMP. By both reverse transcriptase-polymerase chain reaction and immunohistochemistry, endothelial cell NOS and inducible calcium-independent NOS, but not nerve cell NOS, were detected in the ductus arteriosus. Inducible NOS was expressed only by endothelial cells lining the ductus arteriosus lumen; in contrast, endothelial cell NOS was expressed by both luminal and vasa vasorum endothelial cells. The role of inducible NOS in the ductus arteriosus is uncertain because the potency of a specific inducible NOS inhibitor in constricting the ductus arteriosus was negligible compared with that of an endothelial cell NOS inhibitor. We speculate that NO may be an important regulator of ductus arteriosus tone at high but not low PO2. The endothelial cell NOS isoform found in vasa vasorum may be an important source of NO because removal of ductus arteriosus luminal endothelium only partially blocks the effects of L-NAME, methylene blue, and LY83583.
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PMID:Regulation of ductus arteriosus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension, and vasa vasorum. 958 10

Transplanted hearts exhibit depressed contractile function during periods of acute rejection. Myocytes from rejecting hearts also express inducible nitric oxide synthase (iNOS). We hypothesized that an intrinsic defect, due to the increased nitric oxide production by myocytes, is responsible for much of the observed contractile dysfunction. To test our hypothesis, we recorded shortening of myocytes isolated from rejecting (allograft) and non-rejecting (isograft) transplanted rat hearts under control conditions and following exposure to aminoguanidine (an inhibitor of iNOS), or methylene blue (an inhibitor of nitric oxide stimulation of guanylate cyclase). Four days after transplantation, basal shortening was reduced in allograft myocytes compared to isograft myocytes (allografts: 7.0 +/- 0.8 microns; isografts; 10.7 +/- 0.9 microns; P < 0.05). Allograft myocytes also had higher cGMP levels than isograft myocytes (allografts: 0.58 +/- 0.16 pmol/mg protein; isografts: 0.13 +/- 0.08 pmol/mg protein; P < 0.05). Aminoguanidine (1 mM) had no effect on shortening or cGMP levels in isograft myocytes, whereas aminoguanidine significantly reduced cGMP levels and greatly enhanced shortening of allograft myocytes, such that shortening was now similar in allograft and isograft myocytes. Methylene blue (100 microM) also caused a more than three-fold greater increase in shortening of allograft myocytes (+80 +/- 15%) than isograft myocytes (+23 +/- 6%; P < 0.05 from allografts). These results suggest that myocytes isolated from rejecting hearts have a reversible intrinsic contractile depression which is mediated by overstimulation of the nitric oxide/cGMP pathway within the myocytes. This intrinsic contractile dysfunction may be a major factor responsible for the reversible cardiac depression associated with acute rejection of transplanted hearts.
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PMID:Myocytes isolated from rejecting transplanted rat hearts exhibit reduced basal shortening which is reversible by aminoguanidine. 961 41

In recent years, nitric oxide (NO), a single but highly reactive molecule has become known as the central point of many researchs. NO is synthesized by the enzyme nitric oxide synthase (NOS) in mammals from the amino-acid L-arginine. The products of L-arginine oxidation by NOS are L-citrulline and NO. Nitric oxide has a very short half life, is lipid soluble, reacts easily with several enzymatic systems, and is produced by a wide amount of cells. At least, three kinds of enzymes NOS have been described: two of them are calcium-dependent and continuously present in select cells (constitutive NOS, cNOS). One cNOS isoform is present in the cytosol of neuronal cells, while the other isoform is present in membrane-bound form, in endothelial cells. cNOS produces small quantities of NO, following stimulation by specific agonist. NO produced by cNOS frequently mediates cellular communications and cellular signaling. A third isoform is calcium-independent, is not present in unstimulated cells, and produces large quantities of NO following stimulation of the appropriate cell with cytokines or LPS (inducible NOS, iNOS). NO is a mediator of both physiological and pathological process. It acts directly on its targets, one of them, maybe the most important, is the soluble guanylate cyclase, and produces a variety of biological effects, ranged from cytoprotection to cytotoxicity. An analysis of the biochemistry and physiology of NO is the focus of this review, together with its biological action and potential therapeutical implications.
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PMID:[Physiological and physiopathological aspects of nitric acid in mammalian tissues]. 970 23

Nitric oxide (NO) is known to have antiatherogenic and anti-inflammatory properties, but its effects on the cytokine-induced nuclear factor-kappa B (NF-kappaB) activation pathway in relation to the regulation of inducible nitric oxide synthase (iNOS) gene in vascular smooth muscle cells (VSMCs) remain elusive. To elucidate the roles of NO in the regulation of cytokine-induced NF-kappaB activation and consequent iNOS gene expression, we studied the effects of NO donors [(+/-)-(E)-ethyl-2-[(E)-hydroxyamino]-5-nitro-3-hexeneamide (NOR3) and sodium nitroprusside] on interleukin (IL)-1beta-induced NF-kappaB activation and IkappaB-alpha degradation and subsequent iNOS expression in rat VSMCs. Northern blot and Western blot analyses demonstrated that NO donors decreased IL-1beta-induced iNOS mRNA and protein expression. Electrophoretic mobility shift assay using synthetic oligonucleotide corresponding to the downstream NF-kappaB site of rat iNOS promoter as a probe showed that NOR3 inhibited IL-1beta-induced NF-kappaB activation and its nuclear translocation, as demonstrated with immunocytochemical study. These effects were independent of guanylate cyclase activation; an inhibitor of soluble guanylate cyclase (1H-oxadiazolo-1,2,4-[4,3-alpha]quinoxaline-1-one) had no effect on NOR3-induced inhibition of NF-kappaB activation or iNOS mRNA expression by IL-1beta, and a cGMP derivative (8-bromo-cGMP) failed to mimic the effects of NO donors. Western blot analysis using anti-IkappaB-alpha and anti-phospho-IkappaB-alpha antibodies revealed that IL-1beta induced a transient degradation of IkappaB-alpha preceded by a rapid appearance of phosphorylated IkappaB-alpha, both of which were completely blocked by NOR3. A proteasome inhibitor (MG115) blocked IL-1beta-induced transient degradation of IkappaB-alpha and stabilized the appearance of phosphorylated IkappaB-alpha stimulated by IL-1beta. NOR3 inhibited the appearance of IL-1beta-induced phosphorylated IkappaB-alpha even in the presence of MG115. Our results indicate that an inhibitory action by NO on cytokine-induced NF-kappaB activation and iNOS gene expression is due to its direct blockade on phosphorylation and subsequent degradation of IkappaB-alpha via the cGMP-independent pathway in rat VSMCs.
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PMID:NO inhibits cytokine-induced iNOS expression and NF-kappaB activation by interfering with phosphorylation and degradation of IkappaB-alpha. 981 20

Nitric oxide (NO), generated by endothelial (e) NO synthase (NOS) and neuronal (n) NOS, plays a ubiquitous role in the body in controlling the function of almost every, if not every, organ system. Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), induce inducible (i) NOS synthesis that produces massive amounts of NO toxic to the invading viruses and bacteria, but also host cells by inactivation of enzymes leading to cell death. The actions of all forms of NOS are mediated not only by the free radical oxidant properties of this soluble gas, but also by its activation of guanylate cyclase (GC), leading to the production of cyclic guanosine monophosphate (cGMP) that mediates many of its physiological actions. In addition, NO activates cyclooxygenase and lipoxygenase, leading to the production of physiologically relevant quantities of prostaglandin E2 (PGE2) and leukotrienes. In the case of iNOS, the massive release of NO, PGE2, and leukotrienes produces toxic effects. Systemic injection of LPS causes induction of interleukin (IL)-1 beta mRNA followed by IL-beta synthesis that induces iNOS mRNA with a latency of two and four hours, respectively, in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood-brain barrier, and shortly thereafter, in hypothalamic regions, such as the temperature-regulating centers, paraventricular nucleus containing releasing and inhibiting hormone neurons, and the arcuate nucleus, a region containing these neurons and axons bound for the median eminence. We are currently determining if LPS similarly activates cytokine and iNOS production in the cardiovascular system and the gonads. Our hypothesis is that recurrent infections over the life span play a significant role in producing aging changes in all systems outside the blood-brain barrier via release of toxic quantities of NO. NO may be a major factor in the development of coronary heart disease (CHD). Considerable evidence has accrued indicating a role for infections in the induction of CHD and, indeed, patients treated with a tetracycline derivative had 10 times less complications of CHD than their controls. Stress, inflammation, and infection have all been shown to cause induction of iNOS in rats, and it is likely that this triad of events is very important in progression of coronary arteriosclerosis leading to coronary occlusion. Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone, melatonin, respectively, may be caused by NO. The induction of iNOS in the temperature-regulating centers by infections may cause the decreased febrile response in the aged by loss of thermosensitive neurons. iNOS induction in the paraventricular nucleus may cause the decreased nocturnal secretion of growth hormone (GH) and prolactin that occurs with age, and its induction in the arcuate nucleus may destroy luteinizing hormone-releasing hormone (LHRH) neurons, thereby leading to decreased release of gonadotropins. Recurrent infections may play a role in aging of other parts of the brain, because there are increased numbers of astrocytes expressing IL-1 beta throughout the brain in aged patients. IL-1 and products of NO activity accumulate around the plaques of Alzheimer's, and may play a role in the progression of the disease. Early onset Parkinsonism following flu encephalitis during World War I was possibly due to induction of iNOS in cells adjacent to substantia nigra dopaminergic neurons leading to death of these cells, which, coupled with ordinary aging fall out, led to Parkinsonism. The central nervous system (CNS) pathology in AIDS patients bears striking resemblance to aging changes, and may also be largely caused by the action of iNOS. Antioxidants, such as melatonin, vitamin C, and vitamin E, probably play an important acute and chronic role in reducing or eliminating the oxidant damage produced by NO.
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PMID:The nitric oxide hypothesis of aging. 995 25

Liver damage induced by lipopolysaccharide (LPS) in actinomycin D-sensitized mice was initiated by a Fas/CD95-independent apoptotic process that produced DNA fragmentation in hepatocytes followed by an increase of plasma ALT. The metabolic inhibitor actinomycin D blocked most of the LPS-induced increase of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor, N(G)-monomethyl-l-arginine, which also promoted LPS-induced apoptotic liver damage. Administration of nitric oxide donors (hydroxylamine, S-nitroso-N-acetylpenicillamine or 2, 2'-(hydroxynitrosohydrazino)bis-ethanamine) resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. The protective effect of nitric oxide against apoptotic liver damage was partially reproduced by a membrane-permeable analog of cyclic GMP. On the other hand, treatment with the soluble guanylate cyclase inhibitor LY83583 overcame the protective effect of nitric oxide against apoptotic liver damage. These results suggest that nitric oxide may regulate programmed cell death in the mouse liver and that induction of genes, including inducible nitric oxide synthase, plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, via the soluble guanylate pathway.
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PMID:Nitric oxide ameliorates actinomycin D/endotoxin-induced apoptotic liver failure in mice. 1042 31

The effects of exogenous and endogenous. NO on myocardial functions such as contraction, relaxation and heart rate have recently gained considerable scientific interest. .NO stimulates myocardial soluble guanylate cyclase to produce cGMP, which activates two major target proteins. A small increase in cGMP levels predominantly inhibits phosphodiesterase III, while high cGMP levels activate cGMP-dependent protein kinase. Accordingly, submicromolar .NO concentrations improve myocardial contraction, while submillimolar .NO concentrations decrease contractility. The latter action includes direct inhibitory .NO effects on ATP synthesis and voltage-gated calcium channels. Overall, the inotropic effects of exogenous .NO are small and probably of minor importance for myocardial contractility. Cardiomyocytes are capable of expressing eNOS and iNOS. Endogenous .NO has effects on myocardial contraction, similar to that of exogenous .NO. Various NOS inhibitors can substantially reduce myocardial contractility in vitro and in vivo, suggesting that basal endogenous .NO production supports myocardial contractility. There is also evidence for a .NO-dependent cardiodepressive effect of cytokines that is mediated by expression of iNOS. This is consistent with the negative inotropic effects of .NO at high concentrations. Cardiodepressive actions of endogenous .NO production may play a role in certain forms of heart failure. Finally, .NO also has an effect on heart rate. Physiologic .NO concentrations can stimulate heart rate by activating the hyperpolarization-activated inward current (If) and this effect decreases at submillimolar .NO concentrations. In summary, physiological concentrations of .NO increase contractility and heart rate under basal conditions, while high .NO concentrations induce the opposite effects.
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PMID:Regulation of basal myocardial function by NO. 1061 6

The nitric oxide (NO)-cGMP pathway has been proposed as a mechanism for relaxation of myometrium during pregnancy and as a modulator of labor. Carbon monoxide (CO), produced by hemeoxygenases (HO-1 and HO-2), also activates soluble guanylate cyclase to increase cGMP. A recent study reported a large increase in HO-1 and HO-2 proteins during pregnancy, suggesting that the HO-CO pathway may be important in the maintenance of uterine quiescence during pregnancy. In this study we used Western blotting, reverse transcription-polymerase chain reaction, and immunohistochemistry to determine HO-1 and HO-2 expression in nonpregnant, pregnant, and laboring myometrium. Immunolocalization of HO was also compared with endothelial and inducible nitric oxide synthases (eNOS and iNOS). In contrast to HO-1 protein, which was not detected in myometrium, HO-2 protein and mRNA were constitutively expressed, although there were no differences in expression between the groups. eNOS was expressed in endothelial cells but not in myometrial smooth muscle. iNOS protein was not detected in myometrium. These data do not support an up-regulation of HO-1 and HO-2 during pregnancy and are not consistent with a role for NO or a major role for CO in human myometrial quiescence. Our results are also in keeping with HO-2 being an noninducible protein.
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PMID:Hemoxygenase and nitric oxide synthase do not maintain human uterine quiescence during pregnancy. 1048 41

1. The sensitivity of the soluble guanylate cyclase (sGC)-cyclic guanosine-3',5'-monophosphate (cyclic GMP) system to nitric oxide (NO) was investigated in mouse aorta from wild type (WT) and NO synthase (NOS) knockout (KO) animals. 2. The NO donor, spermine-NONOate (SPER-NO) was more potent in aortas from eNOS KO mice compared to WT (pEC50 7.30+/-0.06 and 6.56+/-0.04, respectively; n=6; P<0.05). In contrast, the non-NO based sGC activator, YC-1 was equipotent in vessels from eNOS WT and KO mice. The sensitivity of aortas from nNOS and iNOS KO animals to SPER-NO was unchanged. Forskolin (an adenylate cyclase activator), was equipotent in vessels from eNOS WT and KO animals. 3. The cyclic GMP analogue, 8-Br-cGMP was equipotent in eNOS WT and KO mice (pEC50 4. 38+/-0.04 and 4.40+/-0.05, respectively; n=5; P>0.05). Zaprinast (10-5 M) a phosphodiesterase type V (PDE V) inhibitor, had no effect on the response to SPER-NO in vessels from eNOS WT or KO mice. 4. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 3x10-4 M) increased the potency of SPER-NO in aortas from WT mice (pEC50 6. 64+/-0.02 and 7.37+/-0.02 in the absence and presence of L-NAME, respectively; n=4; P<0.05). 5. In summary, there is increased sensitivity of vessels from eNOS KO animals to NO. Cyclic AMP-mediated dilatation is unchanged, consistent with a specific up-regulation of sGC - cyclic GMP signalling. The functional activity of cyclic GMP-dependent protein kinase (G-kinase) and PDE V was also unchanged, suggesting that sGC is the site of up-regulation. These alterations in the sensitivity of the sGC - cyclic GMP pathway might represent a mechanism for the dynamic regulation of NO bioactivity.
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PMID:Autoregulation of nitric oxide-soluble guanylate cyclase-cyclic GMP signalling in mouse thoracic aorta. 1055 46


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