This Article Full Text Full Text (PDF) All Versions of this Article: 23/2/176    most recent 01.ATV.0000054659.72231.A1v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Hattori, Y. Articles by Kasai, K. Search for Related Content PubMed PubMed Citation Articles by Hattori, Y. Articles by Kasai, K. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Statins Related Collections Gene expression Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:176.)
© 2003 American Heart Association, Inc.

Vascular Biology

HMG-CoA Reductase Inhibitor Increases GTP Cyclohydrolase I mRNA and Tetrahydrobiopterin in Vascular Endothelial Cells

Yoshiyuki Hattori; Nobuo Nakanishi; Kazumi Akimoto; Mika Yoshida; Kikuo Kasai

From the Department of Endocrinology and Metabolism (Y.H., M.Y., K.K.) and the Laboratory of Molecular and Cellular Biology (K.A.), Dokkyo University School of Medicine, Mibu, and the Department of Biochemistry (N.N.), Meikai University School of Dentistry Sakado, Saitama, Japan.

Correspondence to Dr Yoshiyuki Hattori, Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. E-mail yhattori{at}dokkyomed.ac.jp

Objective— Endothelial nitric oxide synthase (eNOS) activity is supported by tetrahydrobiopterin (BH4), which appears to be important for generating protective NO but decreases uncoupling formation of superoxide. We investigated the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, in terms of BH4 metabolism in human umbilical vein endothelial cells (HUVECs).

Methods and Results— We measured the mRNA levels of GTP cyclohydrolase I (GTPCH), the rate-limiting enzyme in the first step of de novo BH4 synthesis, by real-time polymerase chain reaction. The mRNA of GTPCH, as well as of eNOS, was upregulated in HUVECs treated with cerivastatin. This increase was time and dose dependent. Fluvastatin was also observed to enhance GTPCH and eNOS mRNA levels. In parallel with this observation, cerivastatin increased intracellular BH4. Incubating HUVECs with tumor necrosis factor (TNF-) was observed to increase GTPCH mRNA while decreasing eNOS mRNA. In the presence of cerivastatin, the TNF-–mediated increase in GTPCH mRNA was enhanced, and the TNF-–mediated decrease in eNOS mRNA was attenuated. Cerivastatin increased the stability of eNOS mRNA. However, it did not alter the stability of GTPCH mRNA but increased GTPCH gene transcription, as shown by nuclear run-on assays. Preteatment of HUVECs with the selective GTPCH inhibitor, 2,4-diamino-6-hydroxypyrimidine, caused a decrease in intracellular BH4 and decreased citrulline formation after stimulation with ionomycin. Furthermore, the potentiating effect of cerivastatin was decreased by limiting the cellular availability of BH4.

Conclusions— Our data demonstrate that statins elevate GTPCH mRNA, thereby increasing BH4 levels in vascular endothelial cells. In addition to augmenting eNOS expression, statins potentiate GTPCH gene expression and BH4 synthesis, thereby increasing NO production and preventing relative shortages of BH4.

Key Words: statins • cytokines • nitric oxide • tetrahydrobiopterin • endothelial cells

This article has been cited by other articles:

				M. Satoh, S. Fujimoto, S. Arakawa, T. Yada, T. Namikoshi, Y. Haruna, H. Horike, T. Sasaki, and N. Kashihara Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy Nephrol. Dial. Transplant., December 1, 2008; 23(12): 3806 - 3813. [Abstract] [Full Text] [PDF]

				A. Miyazaki-Akita, T. Hayashi, Q. F. Ding, H. Shiraishi, T. Nomura, Y. Hattori, and A. Iguchi 17beta-Estradiol Antagonizes the Down-Regulation of Endothelial Nitric-Oxide Synthase and GTP Cyclohydrolase I by High Glucose: Relevance to Postmenopausal Diabetic Cardiovascular Disease J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 591 - 598. [Abstract] [Full Text] [PDF]

				A. L. Moens and D. A. Kass Tetrahydrobiopterin and Cardiovascular Disease Arterioscler Thromb Vasc Biol, November 1, 2006; 26(11): 2439 - 2444. [Abstract] [Full Text] [PDF]

				M. Satoh, S. Fujimoto, Y. Haruna, S. Arakawa, H. Horike, N. Komai, T. Sasaki, K. Tsujioka, H. Makino, and N. Kashihara NAD(P)H oxidase and uncoupled nitric oxide synthase are major sources of glomerular superoxide in rats with experimental diabetic nephropathy Am J Physiol Renal Physiol, June 1, 2005; 288(6): F1144 - F1152. [Abstract] [Full Text] [PDF]

				M. S. Goligorsky Endothelial cell dysfunction: can't live with it, how to live without it Am J Physiol Renal Physiol, May 1, 2005; 288(5): F871 - F880. [Abstract] [Full Text] [PDF]

				J. P. Khoo, L. Zhao, N. J. Alp, J. K. Bendall, T. Nicoli, K. Rockett, M. R. Wilkins, and K. M. Channon Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension Circulation, April 26, 2005; 111(16): 2126 - 2133. [Abstract] [Full Text] [PDF]

				S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]

				M C Verhaar, P E Westerweel, A J van Zonneveld, and T J Rabelink Free radical production by dysfunctional eNOS Heart, May 1, 2004; 90(5): 494 - 495. [Full Text] [PDF]

				N. J. Alp, M. A. McAteer, J. Khoo, R. P. Choudhury, and K. M. Channon Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 445 - 450. [Abstract] [Full Text]