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1 Anesthesiology, Mayo Clinic, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.
Previous studies suggested that loss of tetrahydrobiopterin (BH4) may play an important role in 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 aorta of apolipoprotein E-deficient mice as compared to wild-type mice after 5 months of Western diet treatment. This increase was further significantly enhanced in apolipoprotein E-deficient mice fed for 9 and 14 months. Removal of the endothelium almost eliminated BH4 levels in wild-type mice but not in apoE-deficient mice suggesting that a major component of increased BH4 synthesis is localized in vascular media of apoE-deficient mice. Oxidative products of BH4 were low and did not differ between wild-type and apolipoprotein E-deficient mice over the course of this study. Increased protein expression and enzymatic activity of GTP-cyclohydrolase I were detected in aortas of apolipoprotein E-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 apolipoprotein E-deficient mice.
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