Published Online
on June 14, 2004

A more recent version of this article appeared on July 13, 2004

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Submitted on October 3, 2003
Revised on March 16, 2004
Accepted on March 22, 2004

Functional Tetrahydrobiopterin Synthesis in Human Platelets

Nicola Franscini PhD, Esther B. Bachli MD, Nenad Blau PhD, Manuel Fischler MD, Roland B. Walter MD, Andreas Schaffner MD, and Gabriele Schoedon PhD^*

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

^* To whom correspondence should be addressed. E-mail: klinsog{at}usz.unizh.ch.

Background--Previous studies have provided evidence for the importance of platelet-derived nitric oxide (NO) for the regulation of hemostasis. Tetrahydrobiopterin (BH₄) is an essential cofactor and regulator of NO synthase activity in the vasculature; however, it is as yet unknown whether platelets dispose over a functional BH₄ synthesis.

Methods and Results--We quantified mRNA expression of genes involved in BH₄ synthesis, measured enzymatic activities, and determined intraplatelet levels of pteridines in platelets from healthy volunteers and from patients treated for prolonged periods of time with glucocorticoids. Freshly isolated platelets from healthy volunteers show functional BH₄ synthesis, as evidenced by the presence of mRNA species and enzymatic activity of GTP cyclohydrolase I (GTPCH), 6-pyruvoyl tetrahydropterin synthase, and sepiapterin reductase. Biopterin was the major intraplatelet pteridine, whereas no neopterin was found. mRNA expression and enzymatic activity of GTPCH were undetectably low in platelets that had been stored for 5 days, and no pteridines were found in these platelets. Freshly isolated platelets from patients treated with glucocorticoids had decreased mRNA expression and activity of GTPCH compared with platelets from healthy volunteers.

Conclusions--Human platelets dispose over a functional de novo BH₄ synthesis. Furthermore, our results indicate the potential of external factors, eg, prolonged storage or glucocorticoid therapy, to significantly affect BH₄ synthesis within platelets. Together, these findings offer new insights into the biology and pathobiology of platelet function in humans.

Key words: tetrahydrobiopterin • platelets • nitric oxide synthase

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