cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells

Ohtsuki, Masatsugu; Shiraishi, Hiroaki; Kato, Takefumi; Kuroda, Risa; Tazawa, Masato; Sumi‐Ichinose, Chiho; Tada, Shin; Udagawa, Yasutoshi; Itoh, Mitsuyasu; Ichinose, Hiroshi; Nagatsu, Toshiharu; Hagino, Yasumichi; Nomura, T.

doi:10.1016/s0024-3205(02)01503-5

Cited by 8 publications

(10 citation statements)

References 37 publications

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“…The results indicate that the inhibition of GCH I activity by NO donors is not related to the reduction of the level of either GCH I mRNA or protein in the short term. We previously reported that cAMP inhibited cytokine-stimulated GCH I activity through the suppression of GCH I mRNA expression in the long term, although contribution of post translational modification to regulation of GCH I activity through the cAMP signaling pathway remained unclear (13). The present data show that cAMP fails to affect the GCH I enzyme activity in the short term.…”

Section: Discussioncontrasting

confidence: 56%

“…Thus, it is conceivable that elucidation of the regulatory mechanism of BH4 production in endothelial cells provides an new insight into the control of vascular tone. We previously reported that cAMP and prostacyclin inhibited cytokine stimulated BH4 biosynthesis and secretion by HUVEC (13). Our results strongly suggested that under inflammatory conditions, an increase in cAMP levels in endothelial cells may exert a regulatory effect on the circulatory system.…”

Section: Introductionsupporting

confidence: 70%

“…2A, 3 mM 8br-cGMP inhibited the GCH I activity significantly within 10 min (GCH I activity at 10 min: control, 42.8 ± 1.7; 3 mM 8br-cGMP, 23.2 ± 1.8; n = 4). We have previously reported that cAMP inhibits cytokine-induced GCH I activity in the long term experiments (13). In the present study, we found that 3 mM 8br-cAMP had no effect on the GCH I activity during a 1-h incubation (Fig.…”

Section: Exogeneously Applied Cgmp Analogue Inhibited Gch I Activity supporting

confidence: 62%

“…It has been reported that in human umbilical vein endothelial cells (HUVEC), the cytokine mixture does not lead to the high output of nitric oxide, that is, induction of iNOS expression, although it induced a marked increase in BH4 synthesis (13). The results suggest that the cytokines do not always produce a simultaneous induction of BH4 synthesis and iNOS expression in the same cells.…”

Section: Introductionmentioning

confidence: 92%

“…Isolated total RNA (2 mg) was reverse-transcribed using oligo (dT) [12][13][14][15][16][17][18] primer. After a 1:25 dilution, quantitative PCR was performed in a GeneAmp 5700 sequence detection system using TaqMan fluorescent probes (PE Biosystems, Norwalk, CT, USA).…”

Section: Mrna Isolation and Real Time Pcrmentioning

confidence: 99%

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cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

et al. 2003

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Abstract. Tetrahydrobiopterin (BH4) acts as an essential cofactor for the enzymatic activity of nitric oxide (NO) synthases. Biosynthesis of the cofactor BH4 starts from GTP and requires 3 enzymatic steps, which include GTP cyclohydrolase I (GCH I) catalysis of the first and ratelimiting step. In this study we examined the effects of cGMP on GCH I activity in human umbilical vein endothelial cells under inflammatory conditions. Exogenous application of the cGMP analogue 8-bromo-cGMP markedly inhibited GCH I activity in the short term, whereas an cAMP analogue had no effect on GCH I activity under the same condition. NO donors, NOR3 and sodium nitroprusside, elevated the intracellular cGMP level and reduced GCH I activity in the short term. This inhibition of GCH I activity was obliterated in the presence of an NO trapper carboxy-PTIO. NO donors had no effect on GCH I mRNA expression in the short term. Moreover, cycloheximide did not alter the inhibition by NO donors of GCH I activity. These findings suggest that stimulation of the cGMP signaling cascade down-regulates GCH I activity through post translational modification of the GCH I enzyme.

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