Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human endothelial cells cultured from umbilical vein (HUVEC) were tested for their ability to synthesize nitric oxide (NO), which has been identified as an endothelium-derived relaxing factor. The synthesis of this free radical (detected as citrulline, which is produced stoichiometrically with NO from arginine) in HUVEC is Ca2+ dependent, is increased sevenfold by the calcium ionophore ionomycin, and accounts for most basal and ionomycin-induced guanosine 3',5'-cyclic monophosphate (cGMP) production. Loading of cells with reduced glutathione (GSH), but not with N-(2-mercaptopropionyl)- glycine (MPG), led to increased citrulline production, both basally and after ionomycin stimulation. When the cells were depleted of GSH by incubation with 1-chloro-2,4-dinitrobenzene (CDNB), citrulline synthesis and cGMP production were inhibited in a concentration-dependent way. CDNB was not cytotoxic and did not inhibit cGMP increase elicited by sodium nitroprusside; cell loading with GSH (but not with MPG) relieved the block of citrulline synthesis. These results suggest that GSH is necessary in HUVEC for NO synthesis rather than for the NO effect on guanylate cyclase.
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PMID:Nitric oxide synthesis is impaired in glutathione-depleted human umbilical vein endothelial cells. 821 28

Soluble guanylyl cyclase (GC) is a heme-containing protein that is a predominant target of nitric oxide (NO). This study examined whether the reductant, ascorbate (ASC), the oxidant, dehydroascorbate (DHAA), or other redox agents modulated the sensitivity of isolated rat coronary arteries to NO-induced vasodilations. Based on NO measurements with a NO-sensitive electrode, NO dilated the arteries with a pEC50 of 8.24 +/- 0.05. The potency of NO was significantly enhanced in the presence of ASC (pEC50 = 8.70 +/- 0.02) but was diminished in the presence of DHAA (pEC50 = 7.91 +/- 0.15). The potency of NO was not affected by other redox agents including dithiothreitol, beta-mercaptoethanol, diamide, 1-chloro-2,4-dinitrobenzene, ferricyanide, or ferrocyanide. Experiments involving the cyclic guanosine monophosphate (cGMP) analog, 8-Br-cGMP, and the phosphodiesterase inhibitor, isobutyl-methylxanthine, indicated that neither ASC nor DHAA has an effect on the degradation or potency of cGMP. ASC and DHAA also failed to affect vasodilations induced by diltiazem or forskolin. However, ASC and DHAA affected the potency of NO in human mesenteric arteries. The results are consistent with other evidence that ASC and DHAA affect the redox state of GC, and through this modulate arterial sensitivity to NO. This suggests that the regulation of the redox state of GC may be an additional site of modulation of the NO/cGMP pathway.
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PMID:Ascorbate and dehydroascorbate modulate nitric oxide-induced vasodilations of rat coronary arteries. 1044 82

In this study, we determined whether minocycline may protect rat cortical cultures against neurotoxicity induced by sphingomyelinase/ceramide and explored the underlying mechanisms. We found that minocycline exerted strong neuroprotective effects against toxicity induced by bacterial sphingomyelinase and synthetic C2 ceramide. Minocycline enhanced the production of nitric oxide (NO) with resultant increases in cellular cGMP content. Consistently, minocycline-dependent neuroprotection was abolished by the nitric oxide synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) and the soluble guanylate cyclase (sGC) inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ). Western blotting revealed that minocycline restored the expression levels of cGMP-dependent protein kinase (PKG)-1, antioxidative thioredoxin-1, and antiapoptotic Bcl-2 that were down-regulated by bacterial sphingomyelinase. Accordingly, the PKG inhibitor KT5823, the thioredoxin reductase inhibitor 1-chloro-2,4-dinitrobenzene (DNCB), and a Bcl-2 inhibitor significantly abolished the minocycline neuroprotection. The minocycline-dependent restoration of Bcl-2 was abolished by L-NAME, ODQ, and KT5823, but not by DNCB, suggesting the involvement of NO/sGC/PKG but not thioredoxin. Furthermore, minocycline-dependent recovery of thioredoxin-1 was PKG-independent. Taken together, our results indicate that minocycline protects rat cortical neurons against bacterial sphingomyelinase/ceramide toxicity via an NO/cGMP/PKG pathway with induction of Bcl-2 and PKG-independent stimulation of thioredoxin-1.
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PMID:Neuroprotective mechanisms of minocycline against sphingomyelinase/ceramide toxicity: Roles of Bcl-2 and thioredoxin. 2118 25