PMID- 12726922
OWN - NLM
STAT- MEDLINE
DCOM- 20030724
LR  - 20231213
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 34
IP  - 10
DP  - 2003 May 15
TI  - Hydrogen peroxide stimulates tetrahydrobiopterin synthesis through the induction 
      of GTP-cyclohydrolase I and increases nitric oxide synthase activity in vascular 
      endothelial cells.
PG  - 1343-52
AB  - Tetrahydrobiopterin (BH4), which is an essential cofactor for nitric oxide 
      synthase (NOS), is generally accepted as an important molecular target for 
      oxidative stress. This study examined whether hydrogen peroxide (H(2)O(2)), one 
      of the reactive oxygen species (ROS), affects the BH4 level in vascular 
      endothelial cells (ECs). Interestingly, the addition of H(2)O(2) to ECs markedly 
      increased the BH4 level, but not its oxidized forms. The H(2)O(2)-induced 
      increase in the BH4 level was blocked by the inhibitor of GTP-cyclohydrolase I 
      (GTPCH), which is the rate-limiting enzyme of BH4 synthesis. Moreover, H(2)O(2) 
      induced the expression of GTPCH mRNA, and the inhibitors of protein synthesis 
      blocked the H(2)O(2)-induced increase in the BH4 level. The expression of the 
      inducible isoform of NOS (iNOS) was slightly induced by the treatment with 
      H(2)O(2). Additionally, the L-citrulline formation from L-arginine, which is the 
      marker for NO synthesis, was stimulated by the treatment with H(2)O(2), and the 
      H(2)O(2)-induced L-citrulline formation was strongly attenuated by NOS or GTPCH 
      inhibitor. These results suggest that H(2)O(2) induces BH4 synthesis via the 
      induction of GTPCH, and the increased BH4 is coupled with NO production by 
      coinduced iNOS. H(2)O(2) appears to be one of the important signaling molecules 
      to regulate the BH4-NOS system.
FAU - Shimizu, Shunichi
AU  - Shimizu S
AD  - Department of Pathophysiology, School of Pharmaceutical Sciences, Showa 
      University, Tokyo, Japan. shun@pharm.showa-u.ac.jp
FAU - Shiota, Kazuhiro
AU  - Shiota K
FAU - Yamamoto, Shinichiro
AU  - Yamamoto S
FAU - Miyasaka, Yoshiyuki
AU  - Miyasaka Y
FAU - Ishii, Masakazu
AU  - Ishii M
FAU - Watabe, Tatsuya
AU  - Watabe T
FAU - Nishida, Motohiro
AU  - Nishida M
FAU - Mori, Yasuo
AU  - Mori Y
FAU - Yamamoto, Toshinori
AU  - Yamamoto T
FAU - Kiuchi, Yuji
AU  - Kiuchi Y
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (DNA Primers)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Oxidants)
RN  - 0 (Biopterins)
RN  - 29VT07BGDA (Citrulline)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 94ZLA3W45F (Arginine)
RN  - BBX060AN9V (Hydrogen Peroxide)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type III)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - EC 1.14.13.39 (Nos3 protein, mouse)
RN  - EC 3.5.4.16 (GTP Cyclohydrolase)
RN  - EGX657432I (sapropterin)
SB  - IM
MH  - Animals
MH  - Arginine/metabolism
MH  - Biopterins/*analogs & derivatives/*metabolism
MH  - Blotting, Northern
MH  - Brain/metabolism
MH  - Cells, Cultured
MH  - Citrulline/metabolism
MH  - DNA Primers/chemistry
MH  - Endothelium, Vascular/*drug effects/enzymology
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - GTP Cyclohydrolase/antagonists & inhibitors/genetics/*metabolism
MH  - Hydrogen Peroxide/*pharmacology
MH  - Mice
MH  - Nitric Oxide/metabolism
MH  - Nitric Oxide Synthase/*metabolism
MH  - Nitric Oxide Synthase Type II
MH  - Nitric Oxide Synthase Type III
MH  - Oxidants/*pharmacology
MH  - Reverse Transcriptase Polymerase Chain Reaction
EDAT- 2003/05/03 05:00
MHDA- 2003/07/25 05:00
CRDT- 2003/05/03 05:00
PHST- 2003/05/03 05:00 [pubmed]
PHST- 2003/07/25 05:00 [medline]
PHST- 2003/05/03 05:00 [entrez]
AID - S0891584903001722 [pii]
AID - 10.1016/s0891-5849(03)00172-2 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2003 May 15;34(10):1343-52. doi: 
      10.1016/s0891-5849(03)00172-2.