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(Circulation Research. 2007;101:830.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Regulation of Tetrahydrobiopterin Biosynthesis by Shear Stress

Julian D. Widder, Wei Chen, Li Li, Sergey Dikalov, Beat Thöny, Kazuyuki Hatakeyama, David G. Harrison

From the Emory University Division of Cardiology (J.D.W., W.C., L.L., S.D., D.G.H.), Department of Medicine, Atlanta, Ga; the Atlanta Veterans Administration Hospital (J.D.W., W.C., L.L., S.D., D.G.H.), Ga; Division of Clinical Chemistry and Biochemistry (B.T.), University Children’s Hospital Zürich, Switzerland; and Department of Surgery (K.H.), University of Pittsburgh, Pa.

Correspondence to David G. Harrison, Division of Cardiology, Emory University, 101 Woodruff Circle, WMBR 319, Atlanta, GA 30322. E-mail dharr02{at}emory.edu

An essential cofactor for the endothelial NO synthase is tetrahydrobiopterin (H₄B). In the present study, we show that in human endothelial cells, laminar shear stress dramatically increases H₄B levels and enzymatic activity of GTP cyclohydrolase (GTPCH)-1, the first step of H₄B biosynthesis. In contrast, protein levels of GTPCH-1 were not affected by shear. Shear did not change protein expression or activity of the downstream enzymes 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase and decreased protein levels of the salvage enzyme dihydrofolate reductase. Oscillatory shear only modestly affected H₄B levels and GPTCH-1 activity. We also demonstrate that laminar, but not oscillatory shear stress, stimulates phosphorylation of GTPCH-1 on serine 81 and that this is mediated by the prime (') subunit of casein kinase 2. The increase in H₄B caused by shear is essential in allowing proper function of endothelial NO synthase because GPTCH-1 blockade with 2,4-diamino-6-hydroxypyrimidine during shear inhibited dimer formation of endothelial NO synthase, increased endothelial cell superoxide production, and prevented the increase in NO production caused by shear. Thus, shear stress not only increases endothelial NO synthase levels but also stimulates production of H₄B by markedly enhancing GTPCH-1 activity via casein kinase 2–dependent phosphorylation on serine 81. These findings illustrate a new function of casein kinase 2 in the endothelium and provide insight into regulation of GTPCH-1 activity.

Key Words: endothelial cell • endothelial NO synthase • GTP cyclohydrolase 1 • shear stress • tetrahydrobiopterin

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