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)

Human coronary and peripheral arteries show endothelial dysfunction in a variety of conditions, including atherosclerosis, hypercholesterolemia, smoking, and hypertension. This dysfunction manifests as a loss of endothelium-dependent vasodilation to acetylcholine infusion or sheer stress, and is typically associated with decreased generation of nitric oxide (NO) by the endothelium. Vitamin C, or ascorbic acid, when acutely infused or chronically ingested, improves the defective endothelium-dependent vasodilation present in these clinical conditions. The mechanism of the ascorbic acid effect is unknown, although it has been attributed to an antioxidant function of the vitamin to enhance the synthesis or prevent the breakdown of NO. In this review, multiple mechanisms are considered that might account for the ability of ascorbate to preserve NO. These include ascorbate-induced decreases in low-density lipoprotein (LDL) oxidation, scavenging of intracellular superoxide, release of NO from circulating or tissue S-nitrosothiols, direct reduction of nitrite to NO, and activation of either endothelial NO synthase or smooth muscle guanylate cyclase. The ability of ascorbic acid supplements to enhance defective endothelial function in human diseases provides a rationale for use of such supplements in these conditions. However, it is first necessary to determine which of the many plausible mechanisms account for the effect, and to ensure that undesirable toxic effects are not present.
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PMID:How does ascorbic acid prevent endothelial dysfunction? 1092 60

Ascorbic acid has been shown to stimulate endothelial nitric oxide (NO) synthesis in a time- and concentration-dependent fashion without affecting NO synthase (NOS) expression or l-arginine uptake. The present study investigates if the underlying mechanism is related to the NOS cofactor tetrahydrobiopterin. Pretreatment of human umbilical vein endothelial cells with ascorbate (1 microm to 1 mm, 24 h) led to an up to 3-fold increase of intracellular tetrahydrobiopterin levels that was concentration-dependent and saturable at 100 microm. Accordingly, the effect of ascorbic acid on Ca(2+)-dependent formation of citrulline (co-product of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) was abolished when intracellular tetrahydrobiopterin levels were increased by coincubation of endothelial cells with sepiapterin (0.001-100 microm, 24 h). In contrast, ascorbic acid did not modify the pterin affinity of endothelial NOS, which was measured in assays with purified tetrahydrobiopterin-free enzyme. The ascorbate-induced increase of endothelial tetrahydrobiopterin was not due to an enhanced synthesis of the compound. Neither the mRNA expression of the rate-limiting enzyme in tetrahydrobiopterin biosynthesis, GTP cyclohydrolase I, nor the activities of either GTP cyclohydrolase I or 6-pyruvoyl-tetrahydropterin synthase, the second enzyme in the de novo synthesis pathway, were altered by ascorbate. Our data demonstrate that ascorbic acid leads to a chemical stabilization of tetrahydrobiopterin. This was evident as an increase in the half-life of tetrahydrobiopterin in aqueous solution. Furthermore, the increase of tetrahydrobiopterin levels in intact endothelial cells coincubated with cytokines and ascorbate was associated with a decrease of more oxidized biopterin derivatives (7,8-dihydrobiopterin and biopterin) in cells and cell supernatants. The present study suggests that saturated ascorbic acid levels in endothelial cells are necessary to protect tetrahydrobiopterin from oxidation and to provide optimal conditions for cellular NO synthesis.
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PMID:L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. 1102 34

Antioxidants and antioxidant enzymes are known to protect against cell death induced by reactive oxygen species. However, apart from directly quenching free radicals, little is known about the effect of antioxidants on hormone-activated second messenger systems. We previously found that antioxidants such as 17-beta estradiol and resveratrol activate membrane-bound guanylate cyclase GC-A, the receptor for atrial natriuretic factor (ANF), in PC12 cells. It is possible that other antioxidants may also activate membrane-bound guanylate cyclase GC-A. The aim of this study was to determine if dithiothreitol (DTT), vitamin C, and vitamin E activate membrane-bound guanylate cyclase GC-A in PC12 cells. The results showed that both DTT and vitamin C increased cGMP levels in PC12 cells, whereas vitamin E had no effect. DTT and vitamin C inhibited membrane-bound guanylate cyclase activity stimulated by ANF in PC12 cells. In contrast, DTT and vitamin C had no effect on soluble guanylate cyclase activity stimulated by substance P. Furthermore, NO synthase inhibitors L-NAME and aminoguanidine did not affect DTT- and vitamin C-stimulated guanylate cyclase activity. The results indicate that DTT and vitamin C, but not vitamin E, activate membrane-bound guanylate cyclase GC-A in PC12 cells.
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PMID:Antioxidants, vitamin C and dithiothreitol, activate membrane-bound guanylate cyclase in PC12 cells. 1127 22

Low-level lead exposure is a known cause of hypertension that has been associated with increased reactive oxygen species activity and endothelial-dependent vasorelaxation impairment. The effect of lead exposure on the vascular nitric oxide (NO)/cyclic guanocine monophosphate (cGMP) system was analyzed. Wistar rats were exposed to 5 ppm lead acetate in the drinking water during 30 d. Mean arterial BP increased significantly in the lead-treated rats. Relaxation to both acetylcholine and sodium nitroprusside (SNP) was reduced in lead-treated rats; however, the vascular wall of lead-administered rats showed an increased expression of endothelial NO synthase. The expression of both subunits (alpha(1) and beta(1)) of soluble guanylate cyclase (sGC) and the cGMP accumulated in the vascular wall were decreased in lead-treated rats. Cotreatment of lead with vitamin C (3 mmol/L) prevented the increase on mean arterial BP, improved the relaxation to both acetylcholine and sodium nitroprusside, and restored the normal expression of endothelial NO synthase and sGC proteins in the vascular wall. In conclusion, lead exposure altered both the endothelium-dependent and -independent relaxing response and induced a reduced expression of sGC in the vascular wall. These effects were abrogated with the antioxidant vitamin C, which suggests the involvement of reactive oxygen species in the regulation of the NO/cGMP relaxing system in the vascular wall of lead-treated rats.
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PMID:Alteration of the soluble guanylate cyclase system in the vascular wall of lead-induced hypertension in rats. 1172 27

Accumulated evidence suggests that quercetin, a dietary flavonoid, has beneficial effects in protection against cardiovascular diseases and in the inhibition of tumour growth. We have recently shown that antioxidants such as 17beta-estradiol, resveratrol, dithiothreitol and vitamin C activate membrane-bound guanylate cyclase GC-A, a receptor for atrial natriuretic factor (ANF). Since quercetin is a phytoestrogen and potent antioxidant, it is possible that it may activate GC-A or other guanylate cyclase isoforms. We examined whether quercetin activates GC-A or GC-B (the receptor for C-type natriuretic peptide, CNP) in PC12 and porcine kidney proximal tubular LLC-PK1 cells. The results showed that quercetin activated a guanylate cyclase isoform in both cell types. Quercetin inhibited CNP-stimulated GC-B activity, but had little effect on ANF-stimulated GC-A activity in PC12 cells, suggesting that quercetin mainly activates GC-B in PC12 cells. In contrast, CNP had no effect on guanylate cyclase activity in LLC-PK1 cells, indicating that GC-B is not expressed in LLC-PK1 cells. Furthermore, quercetin had a small effect on ANF-stimulated GC-A activity and had no effect on soluble guanylate cyclase activity in LLC-PK1 cells, suggesting that quercetin does not activate GC-A, GC-B or soluble guanylate cyclase in LLC-PK1 cells. However, quercetin did stimulate membrane-bound guanylate cyclase activity in LLC-PK1 cell membranes. These results indicate that quercetin activates the GC-B isoform in PC12 cells, but activates an unknown membrane-bound guanylate cyclase isoform in LLC-PK1 cells.
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PMID:Quercetin, a phytoestrogen and dietary flavonoid, activates different membrane-bound guanylate cyclase isoforms in LLC-PK1 and PC12 cells. 1272 41

Lead exposure is a known cause of hypertension. Although most studies have focused on lead-induced endothelial dysfunction and on the involvement of reactive oxygen species (ROS), it has been recently demonstrated that the vascular wall of lead-exposed rats has both an altered the endothelium-independent relaxing response and a reduced expression of soluble guanylate cyclase (sGC). The aim of the present study was to determine in in vitro incubated rat isolated aortic segments if lead downregulates sGC expression, analyzing the involvement of ROS and cyclooxygenase-2 (COX-2). The experiments were performed in isolated aortic segments from Wistar rats that were incubated with lead for 24 h. Lead significantly reduced sGC-beta(1) subunit expression in a concentration-dependent manner. The maximal reduction in sGC-beta(1) subunit expression was achieved with 1 ppm lead. Vitamin C (30 micromol/L) partially restored sGC-beta( 1) subunit expression in lead (1 ppm)-exposed aortic segments. A similar protection of sGC-beta(1) subunit expression was obtained with both a protein kinase A inhibitor, H89 (1 micromol/L) and with rofecoxib (1 micromol/L), an inhibitor of COX-2 activity. Moreover, lead exposure increased COX-2 expression in the arterial wall. While vitamin C reduced both COX-2 expression and superoxide anion production related to lead exposure, rofecoxib failed to modify superoxide anion generation in lead-incubated aortic segments. In conclusion, the present results suggest the involvement of ROS and COX-2 in the downexpression of sGC-beta(1) subunit induced by lead in the rat vascular wall.
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PMID:Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2. 1276 Dec 46

We studied the capability of dimeric forms of dinitrosyl-iron complexes and S-nitrosothiols to activate soluble guanylate cyclase (sGC) from human platelet cytosol. The dinitrosyl-iron complexes had the ligands glutathione (DNIC-GS) or N-acetylcysteine (DNIC-NAC). The S-nitrosothiols were S-nitrosoglutathione (GS-NO) or S-nitrosoacetylcysteine (SNAC). For both glutathione and N-acetylcysteine, the DNIC and S-nitrosothiol forms are equally effective activators of sGC. The activation mechanism is strongly affected by the presence of intrinsic metal ions. Pretreatment with the potent iron chelator, disodium salt of bathophenanthroline disulfonic acid (BPDS), suppressed sGC activation by GS-NO: the concentration of GS-NO producing maximal sGC activation was increased by two orders of magnitude. In contrast, activation by DNIC-GS is strongly enhanced by BPDS. When BPDS was added 10 min after supplementation of DNIC-GS or GS-NO at 4 degrees C, it exerted a similar effect on sGC activation by either NO donor: BPDS only enhanced the sGC stimulation at low concentrations of the NO donors. Our experiments demonstrated that both Fe(2+) and Cu(2+) ions contribute to the decomposition of GS-NO in the presence of ascorbate. The decomposition of GS-NO induced by Fe(2+) ions was accompanied by formation of DNIC. BPDS protected GS-NO against the destructive action of Fe(2+) but not Cu(2+) ions. Additionally, BPDS is a sufficiently strong chelator to remove the iron from DNIC-GS complexes. Based on our data, we propose that S-nitrosothiols activate sGC via a two-step iron-mediated process: In the first step, intrinsic Fe(2+) ions catalyze the formation of DNICs from S-nitrosothiols. In the secondary step, these newly formed DNICs act as the real NO donors responsible for sGC activation.
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PMID:Activation of soluble guanylate cyclase by NO donors--S-nitrosothiols, and dinitrosyl-iron complexes with thiol-containing ligands. 1282 64

Alpha-tocopherol has been shown to increase nitric oxide (NO)-dependent relaxation but the underlying mechanisms have not been fully characterized. The present study investigates the effect of alpha-tocopherol and its derivative trolox on the synthesis of NO in human umbilical vein endothelial cells. NO was assayed as citrulline (co-product of NO) and cGMP (product of the NO-activated soluble guanylate cyclase) on ionomycin stimulation of cells. Ionomycin induced citrulline and cGMP formation partially through phosphorylation of endothelial NO synthase (eNOS) at its serine residue 1177, which was mediated mainly by calmodulin-dependent kinase II. Preincubation of cells with alpha-tocopherol or trolox increased eNOS activity in a concentration-dependent manner without changing eNOS expression. The effect of the water-soluble trolox was due to chemical stabilization of the eNOS cofactor tetrahydrobiopterin. On the contrary, alpha-tocopherol, located mainly in cellular membranes, did not affect tetrahydrobiopterin but increased ionomycin-induced eNOS phosphorylation at serine 1177. The effects of alpha-tocopherol on citrulline and cGMP formation and eNOS phosphorylation were amplified by co-incubation with ascorbate, which is suggested to regenerate oxidized alpha-tocopherol and to act synergistically with alpha-tocopherol. Our data describe a new vasoprotective function of alpha-tocopherol that may contribute to the prevention of endothelial dysfunction in vivo.
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PMID:Alpha-tocopherol amplifies phosphorylation of endothelial nitric oxide synthase at serine 1177 and its short-chain derivative trolox stabilizes tetrahydrobiopterin. 1528 20

Nitric oxide (NO), a central regulator of vascular tone and homeostasis, is generated upon activation of endothelial NO synthase (eNOS), which is mediated by an increase of intracellular calcium and/or by eNOS phosphorylation. A reduction of NO bioavailability leads to endothelial dysfunction that has been shown to be improved by alpha-tocopherol in certain conditions. The underlying mechanisms, however, are not completely clarified. The present study was performed to investigate whether alpha-tocopherol is able to affect endothelial NO synthesis. The formation of NO was measured in human umbilical vein endothelial cells using citrulline (coproduct) and cGMP (product of the NO-activated soluble guanylate cyclase) as indicator molecules. alpha-Tocopherol (10-200 microM, 24 hr) increased ionomycin-induced citrulline and cGMP formation in intact cells in a concentration-dependent manner. In parallel, ionomycin-stimulated phosphorylation of eNOS at serine 1177, known to support enzyme activation, was increased by alpha-tocopherol, suggesting that this was the mechanism responsible for enhanced NO formation. The effect of alpha-tocopherol was dependent on its hydrophobic structure because it was mimicked by gamma-tocopherol but not by trolox, a hydrophilic derivative of alpha-tocopherol. Coincubation with ascorbic acid (100 microM, 24 hr) amplified the effects of alpha-tocopherol on eNOS phosphorylation and NO formation, which is possibly related to the regeneration of oxidized alpha-tocopherol by ascorbate. Our data suggest that vasoprotective effects of alpha-tocopherol in vivo may be related to an increase of NO formation. The effect of alpha-tocopherol seems to be dependent on tissue saturation with ascorbic acid, and both vitamins may act synergistically to provide optimal conditions for endothelial NO formation.
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PMID:Alpha-Tocopherol and endothelial nitric oxide synthesis. 1575 35

Incorporation of a nitric oxide (NO)-releasing moiety in aspirin can overcome its gastric side effects. We investigated the NO-release patterns and antiplatelet effects of novel furoxan derivatives of aspirin (B8 and B7) in comparison to existing antiplatelet agents. Cyclooxygenase (COX) activity was investigated in purified enzyme using an electron paramagnetic resonance-based technique. Concentration-response curves for antiplatelet agents +/- the soluble guanylate cyclase inhibitor, ODQ (50 microM) were generated in platelet-rich plasma (PRP) and washed platelets (WP) activated with collagen using turbidometric aggregometry. NO was detected using an isolated NO electrode. The furoxan derivatives of aspirin (B8, B7) and their NO-free furazan equivalents (B16, B15; all 100 microM) significantly inhibited COX activity (P < 0.01; n = 6) in vitro and caused aspirin-independent, cGMP-dependent inhibition of collagen-induced platelet aggregation in WP. B8 was more potent than B7 (PRP IC(50) = 0.62 +/- 0.1 microM for B8; 400 +/- 89 microM for B7; P < 0.0001. WP IC(50)s = 0.6 +/- 0.1 and 62 +/- 10 microM, respectively). The NO-free furazan counterparts were less potent antiplatelet agents (WP IC(50)s = 54 +/- 3 microM and 62 +/- 10 microM, respectively; P < 0.0001, B8 vs B16). Of the hybrids investigated, only B8 retained antiplatelet activity in PRP.NO release from furoxan-aspirin hybrids was undetectable in buffer alone, but was accelerated in the presence of either plasma or plasma components, albumin (4%), glutathione (GSH; 3 microM) and ascorbate (50 microM), the effects of which were additive for B7 but not B8. NO generation from furoxans was greatly enhanced by platelet extract, an effect that could largely be explained by the synergistic effect of intracellular concentrations of GSH (3 mM) and ascorbate (1 mM). We conclude that the decomposition of furoxan-aspirin hybrids to generate biologically active NO is catalysed by endogenous agents which may instil a potential for primarily intracellular delivery of NO. The blunting of the aspirin effects of furoxan hybrids is likely to be due to loss of the acetyl moiety in plasma; the observed antiplatelet effects are thereby primarily mediated via NO release. Compounds of this class might represent a novel means of inhibiting platelet aggregation by a combination of NO generation and COX inhibition.
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PMID:Mechanism of action of novel NO-releasing furoxan derivatives of aspirin in human platelets. 1670 97


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