From the Medical Clinic B Research Unit (P.L., A.S., G.S.), Department of
Medicine, University Hospital of Zurich, and Department of Pediatrics (N.B.),
Division of Clinical Chemistry and Biochemistry, University Childrens Hospital
of Zurich, Zurich, Switzerland.
Correspondence to PD Dr Gabriele Schoedon, Department of Medicine, University Hospital of Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland. E-mail klinsog{at}usz.unizh.ch
Abstract
Background—The nitric oxide
synthase cofactor tetrahydrobiopterin (BH4) is involved in the
regulation of endothelium-dependent vascular functions
mediated by nitric oxide. Vascular endothelial cells
synthesize and secrete large amounts of BH4 on cytokine
activation. There is scant knowledge about molecular mechanisms of
cytokine-triggered BH4 production in endothelial
cells.
Methods and Results—Pteridine production, mRNA expression
of GTP cyclohydrolase (GTPCH) and 6-pyruvoyltetrahydropterin synthase
(PTPS) (both key enzymes of BH4 biosynthesis), and PTPS activity were
studied in human umbilical vein endothelial cells
(HUVECs) exposed to inflammatory cytokines. BH4 levels were
Conclusions—The present study demonstrates for the first time
the cytokine-dependent regulation of PTPS, the second enzyme in
BH4 synthesis. Although GTPCH is believed to be the rate-limiting step,
control of endothelial PTPS expression by
cytokines may play an important role in regulating
BH4-dependent nitric oxide production in the vascular system.
© 1998 American Heart Association, Inc.
Brief Rapid Communication
Regulation of 6-Pyruvoyltetrahydropterin Synthase Activity and Messenger RNA Abundance in Human Vascular Endothelial Cells
140-fold enhanced on treatment of HUVECs with combined
interferon-
/tumor necrosis factor-
/interleukin-1 (IFN/TNF/IL-1).
Specific PTPS activity was 
3-fold higher in cytokine-treated
HUVECs than in untreated cells. Reverse-transcription/limiting-dilution
polymerase chain reaction analysis showed that in response to
IFN/TNF/IL-1, mRNA abundance of GTPCH and PTPS was increased 64-fold
and 10-fold, respectively.
Key Words: cells • endothelium-derived factors • enzymes • vasculature
This article has been cited by other articles:
 |
|
 |
|
  M. J. Crabtree, A. L. Tatham, A. B. Hale, N. J. Alp, and K. M. Channon Critical Role for Tetrahydrobiopterin Recycling by Dihydrofolate Reductase in Regulation of Endothelial Nitric-oxide Synthase Coupling: RELATIVE IMPORTANCE OF THE DE NOVO BIOPTERIN SYNTHESIS VERSUS SALVAGE PATHWAYS J. Biol. Chem., October 9, 2009; 284(41): 28128 - 28136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Ionova, J. Vasquez-Vivar, J. Whitsett, A. Herrnreiter, M. Medhora, B. C. Cooley, and G. M. Pieper Deficient BH4 production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H2178 - H2187. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Antoniades, C. Shirodaria, T. Van Assche, C. Cunnington, I. Tegeder, J. Lotsch, T. J. Guzik, P. Leeson, J. Diesch, D. Tousoulis, et al. GCH1 Haplotype Determines Vascular and Plasma Biopterin Availability in Coronary Artery Disease: Effects on Vascular Superoxide Production and Endothelial Function J. Am. Coll. Cardiol., July 8, 2008; 52(2): 158 - 165. [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]
|
|
|
|
 |
|
 P. Linscheid, D. Seboek, H. Zulewski, U. Keller, and B. Muller Autocrine/Paracrine Role of Inflammation-Mediated Calcitonin Gene-Related Peptide and Adrenomedullin Expression in Human Adipose Tissue Endocrinology, June 1, 2005; 146(6): 2699 - 2708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Franscini, E. B. Bachli, N. Blau, M.-S. Leikauf, A. Schaffner, and G. Schoedon Gene Expression Profiling of Inflamed Human Endothelial Cells and Influence of Activated Protein C Circulation, November 2, 2004; 110(18): 2903 - 2909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Franscini, E. B. Bachli, N. Blau, M. Fischler, R. B. Walter, A. Schaffner, and G. Schoedon Functional Tetrahydrobiopterin Synthesis in Human Platelets Circulation, July 13, 2004; 110(2): 186 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Alp and K. M. Channon Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 413 - 420. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
|
|
N. Franscini, N. Blau, R. B. Walter, A. Schaffner, and G. Schoedon Critical Role of Interleukin-1{beta} for Transcriptional Regulation of Endothelial 6-Pyruvoyltetrahydropterin Synthase Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): e50 - 53. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Cai, N. J Alp, D. McDonald, I. Smith, J. Kay, L. Canevari, S. Heales, and K. M Channon GTP cyclohydrolase I gene transfer augments intracellular tetrahydrobiopterin in human endothelial cells: effects on nitric oxide synthase activity, protein levels and dimerisation Cardiovasc Res, September 1, 2002; 55(4): 838 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shinozaki, A. Hirayama, Y. Nishio, Y. Yoshida, T. Ohtani, T. Okamura, M. Masada, R. Kikkawa, K. Kodama, and A. Kashiwagi Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress J. Am. Coll. Cardiol., December 1, 2001; 38(7): 1821 - 1828. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Agnoletti, S. Curello, T. Bachetti, F. Malacarne, G. Gaia, L. Comini, M. Volterrani, P. Bonetti, G. Parrinello, M. Cadei, et al. Serum From Patients With Severe Heart Failure Downregulates eNOS and Is Proapoptotic : Role of Tumor Necrosis Factor-{alpha} Circulation, November 9, 1999; 100(19): 1983 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Heller, A. Unbehaun, B. Schellenberg, B. Mayer, G. Werner-Felmayer, and E. R. Werner L-Ascorbic Acid Potentiates Endothelial Nitric Oxide Synthesis via a Chemical Stabilization of Tetrahydrobiopterin J. Biol. Chem., January 5, 2001; 276(1): 40 - 47. [Abstract] [Full Text] [PDF]
|
|