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

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  • Shiraishi Hiroaki
    Department of Pharmacology, School of Medicine, Fujita Health University
  • Kato Taiya
    Department of Internal Medicine, School of Medicine, Fujita Health University
  • Atsuta Koji
    Department of Pharmacology, School of Medicine, Fujita Health University
  • Sumi-Ichinose Chiho
    Department of Pharmacology, School of Medicine, Fujita Health University
  • Ohtsuki Masatsugu
    Department of Internal Medicine, School of Medicine, Fujita Health University
  • Itoh Mitsuyasu
    Department of Internal Medicine, School of Medicine, Fujita Health University
  • Hishida Hitoshi
    Department of Internal Medicine, School of Medicine, Fujita Health University
  • Tada Shin
    Department of Obstetrics and Gynecology, School of Medicine, Fujita Health University
  • Udagawa Yasuhiro
    Department of Obstetrics and Gynecology, School of Medicine, Fujita Health University
  • Nagatsu Toshiharu
    Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University
  • Hagino Yasumichi
    Department of Pharmacology, School of Medicine, Fujita Health University
  • Ichinose Hiroshi
    Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University
  • Nomura Takahide
    Department of Pharmacology, School of Medicine, Fujita Health University

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  • cGMP Inhibits GTP Cyclohydrolase 1 Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

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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.<br>

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