Functional tetrahydrobiopterin synthesis in human platelets.
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.


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.
Franscini
Nicola
N
Medical Clinic B Research Unit, Department of Medicine, University Hospital, Zürich, Switzerland.
Bachli
Esther B
EB
Blau
Nenad
N
Fischler
Manuel
M
Walter
Roland B
RB
Schaffner
Andreas
A
Schoedon
Gabriele
G
D000328:Adult; D000368:Aged; D000429:Alcohol Oxidoreductases / Q000097:blood; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001793:Blood Preservation; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy / Q000556:secondary; D003199:Computer Systems; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006136:GTP Cyclohydrolase / Q000096:biosynthesis / Q000097:blood; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D019798:Neopterin / Q000097:blood; D019761:Phosphorus-Oxygen Lyases / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D005938:Glucocorticoids; D012333:RNA, Messenger; D001708:Biopterins; D019798:Neopterin; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D006136:GTP Cyclohydrolase; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase; C003402:sapropterin