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

元データ 2003-11-01 社団法人 日本薬理学会

概要

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.

著者

Hishida Hitoshi Department Of Internal Medicine Fujita Health University School Of Medicine
Hishida Hitoshi 大阪大学 医学部臨床遺伝子治療学
Hishida H Department Of Cardiology Nagoya Memorial Hospital
Hishida Hitoshi Division Of Cardiology Fujita Health University
Ohtsuki Masatsugu Department of Cardiology, Fujita Health University School of Medicine
Hiramitsu Shinya Cardiology Hiramitsu Heart Clinic
Hishida H Department Of Cardiology Fujita Health University
Nomura Takahide Department of Pharmacology, School of Medicine, Fujita Health University, Japan
Udagawa Yasuhiro Department of Obstetrics and Gynecology, Fujita Health University
Udagawa Yasuhiro Department Of Obstetrics And Gynecology Fujita Health University
Udagawa Yasuhiro Departments Of Obstetrics And Gynecology Fujita Health University
Ohtsuki Masatsugu Department Of Cardiology Fujita Health University School Of Medicine
Ohtsuki Masatsugu Department Of Pharmacology Fujita Health University School Of Medicine
KATO TAIYA Department of Internal Medicine, Fujita Health University
ITOH MITSUYASU Department of Internal Medicine, Fujita Health University
HAGINO Yasumichi Department of Pharmacology, Fujita Health University School of Medicine
Nomura Takahide Department Of Pharmacoloty Fujita Health University School Of Medicine
SHIRAISHI Hiroaki Department of Pharmacology, Fujita Health University School of Medicine
Ichinose Hiroshi Division Of Molecular Genetics Institute For Comerehensive Medical Science Fujita Health University
Shiraishi Hiroaki Departments Of Pharmacology Fujita Health University
Sumi Ichinose Departments Of Pharmacology Fujita Health University
Hishida Hitoshi Cardiovascular Center Nagoya Daini Red Cross Hospital
ATSUTA Koji Departments of Pharmacology Fujita Health University
TADA Shin Departments of Obstetrics and Gynecology Fujita Health University
NAGATSU Toshiharu Division of Molecular Genetics, Institute for Comerehensive Medical Science Fujita Health University
Tada Shin Department Of Obstetrics And Gynecology Fujita Health University
Kato Taiya Departments Of Pharmacology Fujita Health University
Itoh Mitsuyasu Departments Of Pharmacology Fujita Health University
Itoh Mitsuyasu Department Of Internal Medicine Fujita Health University School Of Medicine
Ohtsuki Masatsugu Departments Of Pharmacology Fujita Health University
Ohtsuki Masatsugu 藤田保健衛生大学 内科学
Hiramitsu Shinya Division Of Cardiology Department Of Internal Medicine Fujita Health University School Of Medicine
Nagatsu Toshiharu Division Of Molecular Genetics Institute For Comerehensive Medical Science Fujita Health University
Hagino Yasumichi Departments Of Pharmacology Fujita Health University
Shiraishi Hiroaki Department Of Chemical Engineering & Technology Faculty Of Engineering Kyushu University
Nomura Takahide Department Of Pharmacology School Of Medicine Fujita Health University
Sumi Ichinose Department Of Pharmacology School Of Medicine Fujita Health University
Hishida Hitoshi Department Of Cardiology Fujita Health University School Of Medicine
HAGINO Yasumichi Department of Biochemistry, Nagoya University School of Medicine
Kato Taiya Department of Internal Medicine, Aichi Koseiren Toyota Kosei Hospital, Toyota 470-0396, Japan

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