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This Article Full Text Full Text (PDF) All Versions of this Article: 290/6/H2466    most recent 00366.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (8) Citing Articles via Google Scholar Google Scholar Articles by d'Uscio, L. V. Articles by Katusic, Z. S. Search for Related Content PubMed PubMed Citation Articles by d'Uscio, L. V. Articles by Katusic, Z. S.

Increased vascular biosynthesis of tetrahydrobiopterin in apolipoprotein E-deficient mice

Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 14 April 2005 ; accepted in final form 17 January 2006

Previous studies suggested that loss of tetrahydrobiopterin (BH₄) may play an important role in the pathogenesis of vascular endothelial dysfunction induced by diabetes and hypertension. In contrast, controversial results have been reported regarding BH₄ metabolism in experimental models of atherosclerosis. Therefore, the present study was designed to characterize the expression and activity of GTP-cyclohydrolase I, a rate-limiting enzyme in biosynthesis of BH₄, during atherogenesis. BH₄ levels were significantly increased in atherosclerotic aortas of apolipoprotein E (apoE)-deficient mice as compared with wild-type mice after 5 mo of Western diet treatment. This increase was further significantly enhanced in apoE-deficient mice fed for 9 and 14 mo. Removal of the endothelium almost eliminated BH₄ in wild-type mice but not in apoE-deficient mice, suggesting that a major component of increased BH₄ synthesis is localized in the vascular media of apoE-deficient mice. Oxidative products of BH₄ were low and did not differ between wild-type and apoE-deficient mice over the course of this study. Increased protein expression and enzymatic activity of GTP-cyclohydrolase I were detected in aortas of apoE-deficient mice (P < 0.05), providing molecular mechanisms responsible for elevation of vascular BH₄. In contrast to aortas, we did not detect any change in levels of BH₄ and in GTP-cyclohydrolase I expression in the brain. Our results demonstrate selective increase of intracellular BH₄ levels via elevation of GTP-cyclohydrolase I activity in vascular tissue of apoE-deficient mice.

guanosine 5'-triphosphate-cyclohydrolase I; atherosclerosis

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