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http://purl.uniprot.org/citations/9445252http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/9445252http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/9445252http://www.w3.org/2000/01/rdf-schema#comment"In vascular endothelial cells, tetrahydrobiopterin serves as an essential cofactor required for enzymatic activity of nitric oxide synthase. GTP cyclohydrolase I is the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin. Previous studies have demonstrated that proinflammatory cytokines stimulate production of tetrahydrobiopterin in endothelial cells. Long-term regulation of GTP cyclohydrolase I gene expression in endothelium has not been studied. The present study was designed to determine whether the cytokines tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (INF-gamma), and interleukin-1beta (IL-1beta) stimulate tetrahydrobiopterin synthesis by increasing expression of GTP cyclohydrolase I mRNA in endothelial cells. The relative reverse transcription polymerase chain reaction was used to quantify expression of GTP cyclohydrolase I mRNA in cultured human umbilical vein endothelial cells. Nuclear run-on assay was performed to determine the transcription rate of GTP cyclohydrolase I gene. GTP cyclohydrolase I enzymatic activity and production of tetrahydrobiopterin were measured in cell extracts. After incubation with TNF-alpha (2 microg/mL), INF-gamma (200 U/mL), and IL-1beta (5 U/mL) for 24 hours, significantly increased expression of GTP cyclohydrolase I mRNA was detected. Cytokines increased the transcription rate of GTP cyclohydrolase I 3.6-fold. This increase was associated with increased GTP cyclohydrolase I enzymatic activity and elevation of intracellular levels of tetrahydrobiopterin. An RNA synthesis inhibitor, actinomycin D (2 microg/mL), inhibited cytokine-induced expression of GTP cyclohydrolase I gene. A protein synthesis inhibitor, cycloheximide (0.5 microg/mL), did not affect expression of GTP cyclohydrolase I mRNA but blocked the increase in enzyme activity, as well as production of tetrahydrobiopterin. Incubation of endothelial cells for 24 hours in the presence of 8-bromoadenosine 3':5'-cyclic monophosphate (10[-3] mol/L) did not affect expression of GTP cyclohydrolase I mRNA. These results demonstrate that in vascular endothelial cells, cytokines increase production of tetrahydrobiopterin by stimulating expression of GTP cyclohydrolase I gene. This effect is apparently due to increased transcription rather than stabilization of mRNA. Regulation of GTP cyclohydrolase I gene expression by cytokines may play an important role in control of endothelial nitric oxide synthesis."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.org/dc/terms/identifier"doi:10.1161/01.atv.18.1.27"xsd:string
http://purl.uniprot.org/citations/9445252http://purl.org/dc/terms/identifier"doi:10.1161/01.atv.18.1.27"xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/author"Milstien S."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/author"Milstien S."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/author"Katusic Z.S."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/author"Katusic Z.S."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/author"Stelter A."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/author"Stelter A."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/date"1998"xsd:gYear
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/date"1998"xsd:gYear
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/name"Arterioscler. Thromb. Vasc. Biol."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/name"Arterioscler. Thromb. Vasc. Biol."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/pages"27-32"xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/pages"27-32"xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/title"Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/title"Cytokines stimulate GTP cyclohydrolase I gene expression in cultured human umbilical vein endothelial cells."xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/volume"18"xsd:string
http://purl.uniprot.org/citations/9445252http://purl.uniprot.org/core/volume"18"xsd:string
http://purl.uniprot.org/citations/9445252http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/9445252
http://purl.uniprot.org/citations/9445252http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/9445252
http://purl.uniprot.org/citations/9445252http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/9445252
http://purl.uniprot.org/citations/9445252http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/9445252
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