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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:e50.)
© 2003 American Heart Association, Inc.

Vascular Biology

Critical Role of Interleukin-1ß for Transcriptional Regulation of Endothelial 6-Pyruvoyltetrahydropterin Synthase

Nicola Franscini; Nenad Blau; Roland B. Walter; Andreas Schaffner; Gabriele Schoedon

From the Medical Clinic B Research Unit (N.F., A.S., G.S.), Department of Medicine, University Hospital, Zürich, Switzerland; the Division of Clinical Chemistry and Biochemistry (N.B.,), Department of Pediatrics, University Childrens Hospital, Zürich, Switzerland; and the Clinical Research Division (R.B.W.), Fred Hutchinson Cancer Research Center, Seattle, Wash.

Correspondence to Gabriele Schoedon, PhD, Medical Clinic B Research Unit, Department of Medicine, University Hospital, Rämistrasse100, CH-8091 Zürich, Switzerland. E-mail klinsog{at}usz.unizh.ch

Objective— Synthesis of tetrahydrobiopterin (BH₄), an essential cofactor for nitric oxide synthases, is strongly induced on immunostimulation in vascular endothelial cells (VECs). Expression of GTP cyclohydrolase I (GTPCH), the first enzyme in BH₄ biosynthesis, is regulated by cytokines and considered rate-limiting. Herein we investigated the molecular mechanism and relevance of cytokine-dependent regulation of 6-pyruvoyltetrahydropterin synthase (PTPS), the second enzyme in BH₄ synthesis, in human coronary artery endothelial cells (HCAECs).

Methods and Results— Real-time polymerase chain reaction revealed a 4-fold induction of PTPS and a 300-fold induction of GTPCH expression by interleukin (IL)-1ß/tumor necrosis factor-/interferon-, mainly through de novo transcription. On immunostimulation, PTPS became rate-limiting. Importantly, IL-1ß induced PTPS rather than GTPCH. As a result, IL-1ß contributed significantly to the amount of BH₄ produced (+40%) but concomitantly reduced the accumulation of the GTPCH intermediate, 7,8-dihydroneopterin triphosphate (-50%).

Conclusion— Our data show that PTPS induction is necessary for optimized BH₄ synthesis in cytokine-stimulated HCAECs and point to IL-1ß as a leading cytokine in this process.

Key Words: endothelium • interleukin-1ß • nitric oxide synthase • tetrahydrobiopterin

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