[Regulations and pathophysiological significance of the biosynthesis of tetrahydrobiopterin in human endothelial cells].
Tetrahydrobiopterin(BH4) serves as an essential cofactor for the biosynthesis of nitric oxide (NO). BH4 is de novo synthesized from GTP and GTP cyclohydrolase I(GCH I) is the rate-limiting enzyme in the biosynthesis of BH4. Under inflammatory conditions, it is reported that endothelial cells release large amount of BH4. In this study, we examined the regulation mechanism of the biosynthesis of BH4 in human umbilical vein endothelial cells(HUVEC). Prostacyclin and forskolin, reagents of stimulation of cAMP signaling cascade, reduced cytokine induced biosynthesis of BH4 through the inhibition of expression of GCH I mRNA. On the other hand, stimulations of NO-cGMP signaling pathway inhibited GCH I activities through the post translational modification of GCH I enzyme. Both two signaling cascade lead to vasodilation. It is suggested that the biosynthesis of BH4 can be regulated by negative feed back regulation systems between endothelium and smooth muscle cells to prevent over stimulated vasodilation.
Shiraishi
Hiroaki
H
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake 470-1192, Japan.
Ohtsuki
Masatsugu
M
Sumi-Ichinose
Chiho
C
Nomura
Takahide
T
D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D006136:GTP Cyclohydrolase / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology*; D014471:Umbilical Veins; D014664:Vasodilation / Q000502:physiology*
D001708:Biopterins; D009569:Nitric Oxide; D011464:Epoprostenol; D000242:Cyclic AMP; D006136:GTP Cyclohydrolase; C003402:sapropterin; D006152:Cyclic GMP