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(Hypertension. 2009;53:189.)
© 2009 American Heart Association, Inc.

Original Articles

Guanosine Triphosphate Cyclohydrolase I Expression and Enzymatic Activity Are Present in Caveolae of Endothelial Cells

Timothy E. Peterson; Livius V. d'Uscio; Sheng Cao; Xiao-Li Wang; Zvonimir S. Katusic

From the Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics (T.E.P., L.V.d., Z.S.K.) and Divisions of Gastroenterology (S.C.) and Cardiovascular Diseases (X.-L.W.), Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minn.

Correspondence to Zvonimir S. Katusic or Livius V. d'Uscio, Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail Katusic.Zvonimir{at}mayo.edu or dUscio.Livius@mayo.edu

Tetrahydrobiopterin is an essential cofactor required for the synthesis of NO. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin production in endothelial cells, yet little is known about the subcellular localization of this enzyme. In this study, we demonstrated that GTPCH I is localized to caveolar membrane microdomains along with caveolin-1 and endothelial NO synthase. GTPCH I activity was detected in isolated caveolar membranes from cultured endothelial cells. Confocal and electron microscopy analyses confirmed GTPCH I colocalization with caveolin-1. Consistent with in vitro studies, GTPCH I activity was evident in isolated caveolar microdomains from lung homogenates of wild-type mice. Importantly, a 2-fold increase in GTPCH I activity was detected in the aortas of caveolin-1–deficient mice, suggesting that caveolin-1 may be involved in the control of GTPCH I enzymatic activity. Indeed, overexpression of caveolin-1 inhibits GTPCH I activity, and tetrahydrobiopterin biosynthesis is activated by the disruption of caveolae structure. These studies demonstrate that GTPCH I is targeted to caveolae microdomains in vascular endothelial cells, and tetrahydrobiopterin production occurs in close proximity to endothelial NO synthase. In addition, our findings provide new insights into the regulation of GTPCH I activity by the caveolar coat protein, caveolin-1.

Key Words: GTP-cyclohydrolase I • tetrahydrobiopterin • endothelium • caveolin-1 • nitric oxide

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