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

• Main Authors: Hiroaki Shiraishi (Author), Taiya Kato (Author), Koji Atsuta (Author), Chiho Sumi-Ichinose (Author), Masatsugu Ohtsuki (Author), Mitsuyasu Itoh (Author), Hitoshi Hishida (Author), Shin Tada (Author), Yasuhiro Udagawa (Author), Toshiharu Nagatsu (Author), Yasumichi Hagino (Author), Hiroshi Ichinose (Author), Takahide Nomura (Author)
• Format: Book
• Published: Elsevier, 2003-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 rate-limiting 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.

Item Description

1347-8613
10.1254/S1347-8613(19)32575-7