cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
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.
Shiraishi
Hiroaki
H
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan.
Kato
Taiya
T
Atsuta
Koji
K
Sumi-Ichinose
Chiho
C
Ohtsuki
Masatsugu
M
Itoh
Mitsuyasu
M
Hishida
Hitoshi
H
Tada
Shin
S
Udagawa
Yasuhiro
Y
Nagatsu
Toshiharu
T
Hagino
Yasumichi
Y
Ichinose
Hiroshi
H
Nomura
Takahide
T
D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D001708:Biopterins; D006136:GTP Cyclohydrolase; C003402:sapropterin; D006152:Cyclic GMP