This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 52/3/484    most recent HYPERTENSIONAHA.108.112094v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, S. Articles by Zou, M.-H. Search for Related Content PubMed PubMed Citation Articles by Wang, S. Articles by Zou, M.-H. Related Collections Endothelium/vascular type/nitric oxide

(Hypertension. 2008;52:484.)
© 2008 American Heart Association, Inc.

Original Articles

Acute Inhibition of Guanosine Triphosphate Cyclohydrolase 1 Uncouples Endothelial Nitric Oxide Synthase and Elevates Blood Pressure

Shuangxi Wang; Jian Xu; Ping Song; Yong Wu; Junhua Zhang; Hyoung Chul Choi; Ming-Hui Zou

From the Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City.

Correspondence to Ming-Hui Zou, Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, BSEB 325, 941 Stanton L. Young Blvd, Oklahoma City, OK 73104. E-mail ming-hui-zou{at}ouhsc.edu

GTP cyclohydrolase 1 (GTPCH1) is the rate-limiting enzyme in de novo synthesis of tetrahydrobiopterin (BH4), an essential cofactor for endothelial NO synthase (eNOS) dictating, at least partly, the balance of NO and superoxide produced by this enzyme. The aim of this study was to determine the effect of acute inhibition of GTPCH1 on BH4, eNOS function, and blood pressure (BP) in vivo. Exposure of bovine or mouse aortic endothelial cells to GTPCH1 inhibitors (2,4-diamino-6-hydroxypyrimidine or N-acetyl-serotonin) or GTPCH1 small-interference RNA (siRNA) significantly reduced BH4 and NO levels but increased superoxide levels. This increase was abolished by sepiapterin (BH4 precursor) or N^G-nitro-L-arginine methyl ester (nonselective NOS inhibitor). Incubation of isolated murine aortas with 2,4-diamino-6-hydroxypyrimidine or N-acetyl-serotonin impaired acetylcholine-induced endothelium-dependent relaxation but not endothelium-independent relaxation. Aortas from GTPCH1 siRNA-injected mice, but not their control-siRNA injected counterparts, also exhibited impaired endothelium-dependent relaxation. BH4 reduction induced by GTPCH1 siRNA injection was associated with increased aortic levels of superoxide, 3-nitrotyrosine, and adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion molecule 1), as well as a significantly elevated systolic, diastolic, and mean BP in C57BL6 mice. GTPCH1 siRNA was unable to elicit these effects in eNOS^–/– mice. Sepiapterin supplementation, which had no effect on high BP in eNOS^–/– mice, partially reversed GTPCH1 siRNA–induced elevation of BP in wild-type mice. In conclusion, GTPCH1 via BH4 maintains normal BP and endothelial function in vivo by preserving NO synthesis by eNOS.

Key Words: hypertension • NO • superoxide anions • endothelial NO synthase • tetrahydrobiopterin • GTP-cyclohydrolase 1 • oxidative stress

This article has been cited by other articles:

				J. Xu and M.-H. Zou Molecular Insights and Therapeutic Targets for Diabetic Endothelial Dysfunction Circulation, September 29, 2009; 120(13): 1266 - 1286. [Full Text] [PDF]

				J. Xu, S. Wang, Y. Wu, P. Song, and M.-H. Zou Tyrosine Nitration of PA700 Activates the 26S Proteasome to Induce Endothelial Dysfunction in Mice With Angiotensin II-Induced Hypertension Hypertension, September 1, 2009; 54(3): 625 - 632. [Abstract] [Full Text] [PDF]

				S. Wang, J. Xu, P. Song, B. Viollet, and M.-H. Zou In Vivo Activation of AMP-Activated Protein Kinase Attenuates Diabetes-Enhanced Degradation of GTP Cyclohydrolase I Diabetes, August 1, 2009; 58(8): 1893 - 1901. [Abstract] [Full Text] [PDF]