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 present study was designed to analyze the effect of long-term incubation with interleukin-1beta (IL-1beta) on endothelium-dependent relaxation in rat mesenteric resistance arteries. Vessels were incubated in culture medium with or without IL-1beta (10 ng/ml, 14 h). Changes in lumen diameter were recorded in a pressure myograph. Protein expression, nitrite, and superoxide anion (O(2)(.)) production were evaluated by either Western blot or immunofluorescence, Griess reaction, and ethidium fluorescence, respectively. IL-1beta impaired acetylcholine (ACh) and sodium nitroprusside (SNP) vasodilation and increased nitrite and O(2)(.) production and inducible nitric-oxide synthase (iNOS), xanthine oxidase, and p22(phox) expression. However, neither endothelial nitric-oxide synthase (NOS) nor soluble guanylate cyclase protein expression were affected by IL-1beta treatment. Polyethylene glycol superoxide dismutase partially reversed the impairment of ACh relaxation and abolished the O(2)(.) production observed in IL-1beta-treated arteries. The impairment of ACh relaxation induced by IL-1beta was also partially reversed by the xanthine oxidase inhibitor allopurinol (1 mM) but not by either the NADPH oxidase inhibitor apocynin (0.3 mM) or the inducible NOS inhibitor N-3-aminomethylbenzylacetamidine (1 microM). However, all these inhibitors improved the impaired SNP response. The results of the present study demonstrate that long-term incubation with IL-1beta induces an impairment of the nitric oxide-mediated relaxation in mesenteric resistance arteries through the production of O(2)(.), mainly from xanthine oxidase.
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PMID:Increased superoxide anion production by interleukin-1beta impairs nitric oxide-mediated relaxation in resistance arteries. 1618 7

Nitric oxide (NO) derived from the endothelial NO synthase (eNOS) contributes to regulation of cerebral circulation, whereas that produced by neuronal NOS (nNOS) participates in the regulation of brain function. In particular, NO plays an important role in modulation of sympathetic activity and hence central regulation of arterial pressure. Superoxide derived from NAD(P)H oxidase avidly reacts with and inactivates NO and, thereby, modulates its bioavailability. Calmodulin (CM) is required for activation of NOS and soluble guanylate cyclase (sGC) serves as a NO receptor. Superoxide is dismutated to H2O2 by superoxide dismutase (SOD) and H2O2 is converted to H2O by catalase or glutathione peroxidase (GPX). Given the importance of NO in the regulation of brain perfusion and function, we undertook the present study to determine the relative expressions of immunodetectable nNOS, eNOS, CM, sGC, NAD(P)H oxidase and SOD by Western analysis in different regions of the normal rat brain. nNOS was abundantly expressed in the pons cerebellum and hypothalamus and less so in the cortex and medulla. sGC abundance was highest in the hypothalamus and pons, and lowest in the cerebellum and medulla. eNOS and calmodulin were equally abundant in all regions. NAD(P)H oxide was most abundant in the pons compared to other regions. Cytoplasmic SOD was equally distributed among different regions but catalase and GPX were more abundant in pons, hypothalamus and medulla and less so in the cortex and cerebellum. Thus, the study documented regional distributions of NOS, NAD(P)H oxidase, antioxidant enzymes, sGC and calmodulin which collectively regulate production and biological activities of NO and superoxide, the two important small molecular size signaling molecules.
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PMID:Regional expression of NO synthase, NAD(P)H oxidase and superoxide dismutase in the rat brain. 1719 79

This study examined the effect of leptin on renal ouabain-resistant Na(+)-ATPase, which drives the reabsorption of about 10% of sodium transported in the proximal tubule. Chronic leptin administration (0.25 mg/kg s.c. twice daily for seven days) increased Na(+)-ATPase activity by 62.9%. This effect was prevented by the coadministration of superoxide dismutase mimetic, tempol, or the NADPH oxidase inhibitor, apocynin (2 mM in the drinking water). Acutely administered NO donors decreased Na(+)-ATPase activity. This effect was abolished by soluble guanylate cyclase inhibitor, ODQ, but not by protein kinase G inhibitors. Exogenous cGMP reduced Na(+)-ATPase activity, but its synthetic analogues, 8-bromo-cGMP and 8-pCPT-cGMP, were ineffective. The inhibitory effect of NO donors and cGMP was abolished by EHNA, an inhibitor of cGMP-stimulated phosphodiesterase (PDE2). Exogenous cAMP analogue and dibutyryl-cAMP increased Na(+)-ATPase activity and abolished the inhibitory effect of cGMP. Finally, the administration of superoxide-generating mixture (xanthine oxidase+hypoxanthine) increased Na(+)-ATPase activity. The results suggest that nitric oxide decreases renal Na(+)-ATPase activity by stimulating cGMP, which in turn activates PDE2 and decreases cAMP concentration. Increased production of reactive oxygen species may lead to the elevation of Na(+)-ATPase activity by scavenging NO and limiting its inhibitory effect. Chronic hyperleptinemia is associated with increased Na(+)-ATPase activity due to excessive oxidative stress.
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PMID:Regulation of renal ouabain-resistant Na+-ATPase by leptin, nitric oxide, reactive oxygen species, and cyclic nucleotides: implications for obesity-associated hypertension. 1749 45

We investigated the effects of the 5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b] pyridin-3-yl]-pyrimidin-4-ylamine (BAY 41-2272) on the NADPH oxidase activity, gp91(phox) gene expression, cyclic guanosine-3',5'-monophosphate (cGMP) and cyclic adenosine-3',5'-monophosphate (cAMP) levels in the human myelomonocytic THP-1 cell line. THP-1 cells treated with BAY 41-2272 (0.3-10 microM) for 48 h significantly increased the superoxide anion (O(2)(*-)) release. This increase was not affected when cells were pre-treated with the specific cGMP-phosphodiesterase inhibitor zaprinast, the soluble guanylate cyclase inhibitor 1H-[1,2,4] oxidiazolo[4,3-alpha] quinoxalin-1-one (ODQ), the adenylate cyclase inhibitor 9-(tetrahydro-2-furanyl) adenine (SQ 22,536) or the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME). In addition, BAY 41-2272 (3 and 10 microM; 48 h) was able to increase gp91(phox) gene expression on THP-1 cells. The pre-treatment with zaprinast, 3-isobutyl-l-methyl-xanthine (IBMX; 0.5 mM), ODQ, SQ 22,536 or l-NAME caused no additional effect on the expression of gp91(phox) evoked by BAY 41-2272. Treatment of THP-1 cells with BAY 41-2272 caused a significant increase in cGMP and cAMP levels. Our findings show that BAY 41-2272 caused a significant increase on the O(2)(*-) release and gp91(phox) gene expression by THP-1 cells, and an elevation of intracellular cGMP and cAMP levels. However, we could not detect a clear correlation between both O(2)(*-) release and gp91(phox) gene expression with activation of cGMP and cAMP signaling pathways.
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PMID:Effects of BAY 41-2272, an activator of nitric oxide-independent site of soluble guanylate cyclase, on human NADPH oxidase system from THP-1 cells. 1749 38

The constitutive isoform of heme oxygenase, HO-2, is highly expressed in the brain and in cerebral vessels. HO-2 functions in the brain have been evaluated using pharmacological inhibitors of the enzyme and HO-2 gene deletion in in vivo animal models and in cultured cells (neurons, astrocytes, cerebral vascular endothelial cells). Rapid activation of HO-2 via post-translational modifications without upregulation of HO-2 expression or HO-1 induction coincides with the increase in cerebral blood flow aimed at maintaining brain homeostasis and neuronal survival during seizures, hypoxia, and hypotension. Pharmacological inhibition or gene deletion of brain HO-2 exacerbates oxidative stress induced by seizures, glutamate, and inflammatory cytokines, and causes cerebral vascular injury. Carbon monoxide (CO) and bilirubin, the end products of HO-catalyzed heme degradation, have distinct cytoprotective functions. CO, by binding to a heme prosthetic group, regulates the key components of cell signaling, including BK(Ca) channels, guanylyl cyclase, NADPH oxidase, and the mitochondria respiratory chain. Cerebral vasodilator effects of CO are mediated via activation of BK(Ca) channels and guanylyl cyclase. CO, by inhibiting the major components of endogenous oxidant-generating machinery, NADPH oxidase and the cytochrome C oxidase of the mitochondrial respiratory chain, blocks formation of reactive oxygen species. Bilirubin, via redox cycling with biliverdin, is a potent oxidant scavenger that removes preformed oxidants. Overall, HO-2 has dual housekeeping cerebroprotective functions by maintaining autoregulation of cerebral blood flow aimed at improving neuronal survival in a changing environment, and by providing an effective defense mechanism that blocks oxidant formation and prevents cell death caused by oxidative stress.
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PMID:Cerebroprotective functions of HO-2. 1828 71

Endothelial dysfunction in the setting of cardiovascular risk factors such as hypercholesterolemia, diabetes mellitus, chronic smoking, as well hypertension, is, at least in part, dependent of the production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO). ROS-producing enzymes involved in increased oxidative stress within vascular tissue include NADPH oxidase, xanthine oxidase, and mitochondrial superoxide producing enzymes. Superoxide produced by the NADPH oxidase may react with NO, thereby stimulating the production of the NO/superoxide reaction product peroxynitrite. Peroxynitrite in turn has been shown to uncouple eNOS, therefore switching an antiatherosclerotic NO producing enzyme to an enzyme that may accelerate the atherosclerotic process by producing superoxide. Increased oxidative stress in the vasculature, however, is not restricted to the endothelium and also occurs within the smooth muscle cell layer. Increased superoxide production has important consequences with respect to signaling by the soluble guanylate cyclase and the cGMP-dependent kinase I, which activity and expression is regulated in a redox-sensitive fashion. The present review will summarize current concepts concerning eNOS uncoupling, with special focus on the role of tetrahydrobiopterin in mediating eNOS uncoupling.
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PMID:Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. 1832 Dec 9

We have previously demonstrated that the induction of haem oxygenase-1 (EC 1.14.99.3) plays a protective role for soybean plants against cadmium and UV-B stress. Here, we have investigated the possible signal transduction pathways involved in haem oxygenase-1 induction in leaves of soybean plants subjected to salt stress. Treatment with 100 mM NaCl during 48 h increased thiobarbituric acid reactive substances by 30%, whereas GSH decreased by 50%, with respect to controls. These effects were prevented by pre-incubation with diphenyleneiodonium (DPI; an NADPH oxidase inhibitor), [1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; a guanylate cyclase inhibitor) or LaCl3 (calcium channel blocker). NaCl at 100 mM produced in situ accumulation of H2O2 and O2*-, which were also prevented by DPI, ODQ or LaCl3. Moreover, salt-induced haem oxygenase-1 activity was also totally abolished by pretreatment with the different inhibitors. These results clearly demonstrated that the signal transduction pathways involved in oxidative stress triggered by salt stress were similar to those implicated in haem oxygenase-1 induction, and provide additional information suggesting that haem oxygenase might play a key role in the antioxidative protection machinery of higher plants.
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PMID:Signal transduction pathways and haem oxygenase induction in soybean leaves subjected to salt stress. 1901 65

Hyperaldosteronism is associated with impaired endothelium-dependent vascular reactivity owing to increased reactive oxygen species and decreased bioavailable nitric oxide (NO(.)); however, the effects of aldosterone on vasodilatory signaling pathways in vascular smooth muscle cells (VSMC) remain unknown. Soluble guanylyl cyclase (GC) is a heterodimer that is activated by NO(.) to convert cytosolic GTP to cGMP, a second messenger required for normal VSMC relaxation. Here, we show that aldosterone (10(-9)-10(-7) mol/liter) diminishes GC activity by activating NADPH oxidase in bovine aortic VSMC to increase reactive oxygen species levels and induce oxidative posttranslational modification(s) of Cys-122, a beta(1)-subunit cysteinyl residue demonstrated previously to modulate NO(.) sensing by GC. In VSMC treated with aldosterone, Western immunoblotting detected evidence of GC beta(1)-subunit disulfide bonding, whereas mass spectrometry analysis of a homologous peptide containing the Cys-122-bearing sequence exposed to conditions of increased oxidant stress confirmed cysteinyl sulfinic acid (m/z 435), sulfonic acid (m/z 443), and disulfide (m/z 836) bond formation. The functional effect of these modifications was examined by transfecting COS-7 cells with wild-type GC or mutant GC containing an alanine substitution at Cys-122 (C122A). Exposure to aldosterone or hydrogen peroxide (H(2)O(2)) significantly decreased cGMP levels in cells expressing wild-type GC. In contrast, aldosterone or H(2)O(2) did not influence cGMP levels in cells expressing the mutant C122A GC, confirming that oxidative modification of Cys-122 specifically impairs GC activity. These findings demonstrate that pathophysiologically relevant concentrations of aldosterone increase oxidant stress to convert GC to an NO(.)-insensitive state, resulting in disruption of normal vasodilatory signaling pathways in VSMC.
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PMID:Aldosterone increases oxidant stress to impair guanylyl cyclase activity by cysteinyl thiol oxidation in vascular smooth muscle cells. 1914 18

Lysimachia clethroides is widely used in traditional herbal medicine for many purposes, especially for blood vessel-related diseases in Korea and East Asia. Experiments were undertaken to determine whether hydro-alcoholic extract obtained from L. clethroides (LCE) has vasorelaxant activity in the rat aorta rings and, if so, to elucidate the underlying mechanism. Rat aorta rings were suspended in organ chambers for the measurement of changes in isometric tension in the presence or absence of several inhibitors. LCE induced endothelium-dependent vasodilation (ED50 = 6.1 mug/mL) and that was abolished by nitric oxide synthase inhibitor, N-nitro-L-arginine, and guanylyl cyclase inhibitor, 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one, PI3-kinase inhibitor, wortmannin, and cell permeable superoxide dismutase. In addition, LCE decreased vessels contraction by phenylephrine. Prostaglandin synthesis inhibitor, indometacin, and inhibitors of endothelium-derived hyperpolarizing factor, charybdotoxin plus apamin, did not affect vasodilatory effect of LCE. In cultured endothelial cells, LCE-induced phosphorylation of serine 1177-endothelial nitric oxide synthase and serine 473-Akt. LCE inhibited strongly nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in smooth muscle cells and angiotensin II-induced contraction of rat aorta. Finally, increased oxidative stress in rat aorta-induced by angiotensin II is ameliorated by LCE. Taken together, LCE induces an endothelium-dependent vasodilation and might be involved, at least in part, the activation of the nitric oxide-cyclic guanosine monophosphate pathway. In addition, LCE decreases oxidative stress in aorta by inhibition of NADPH oxidase activity. The present findings indicate that LCE could be a candidate of herbal medicine for cardiovascular diseases associated with disturbed NO production and endothelial dysfunction.
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PMID:Lysimachia clethroides extract promote vascular relaxation via endothelium-dependent mechanism. 2016 88

The aim of the present study was to examine the effect of an early stage of streptozotocin-induced diabetes on the mechanism(s) of endothelium-dependent relaxation. Diabetes was induced by a single injection of streptozotocin (48 mg/kg iv), and the ACh-induced relaxation of rat carotid arteries was examined 6 wk later. A diabetes-induced increase in superoxide levels, determined by L-012-induced chemiluminescence, from carotid arteries was associated with endothelial nitric oxide (NO) synthase (eNOS) uncoupling and increased catalytic subunit of NADPH oxidase expression. The sensitivity and maximum response to ACh were similar in normal and diabetic rats despite a decrease in NO release detected by 4-amino-5-methylamino-2',7'-difluorofluorescein. In normal rats, N-nitro-l-arginine (100 microM) plus 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (10 microM), to inhibit NOS and soluble guanylate cyclase (sGC), respectively, abolished ACh-induced relaxation, whereas in diabetic rats, the maximum relaxation to ACh was attenuated (maximum relaxation: 25 + or - 5%), but not abolished, by that treatment. The remaining ACh-induced relaxation was abolished by NO scavengers, cupric chloride (to degrade nitrosothiols), or blockers of endothelial K(+) channels. Western blot analysis of the carotid arteries indicated that diabetes significantly increased the expression of eNOS but decreased the proportion of eNOS expressed as the dimer. These findings demonstrate that in early diabetes, ACh-induced relaxation is maintained but is resistant to NOS inhibition. In early diabetes, nitrosothiol-mediated opening of K(+) channels may act in conjunction with NO stimulation of sGC to maintain endothelium-dependent relaxation despite the increase in vascular superoxide levels.
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PMID:Short-term type 1 diabetes alters the mechanism of endothelium-dependent relaxation in the rat carotid artery. 2054 87


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