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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1493.)
© 2007 American Heart Association, Inc.

Editorials

Endothelial GTPCH in eNOS Uncoupling and Atherosclerosis

Tohru Fukai

From the Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago.

Correspondence Tohru Fukai, MD, PhD, Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, University of Illinois at Chicago, 835 S. Wolcott, M/C868, E403MSB, Chicago, IL 60612. E-mail tfukai@uic.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Nitric oxide (NO) produced from endothelial NO synthase (eNOS) has antiatherosclerotic properties, including inhibition of cell growth, leukocyte adhesion, and platelet adherence and aggregation.¹ NO bioavailability is decreased in various cardiovascular diseases such as hypercholesterolemia and atherosclerosis attributable to reduced NO synthesis and increased NO consumption by reactive oxygen species (ROS).² A critical determinant of eNOS activity is its cofactor tetrahydrobiopterin (BH4),^3,4 which facilitates electron transfer from the eNOS reductase domain and maintains the heme prosthetic group in its redox active form.⁵ Moreover, BH4 promotes and stabilizes eNOS protein monomers into the active homodimeric form of the enzyme.⁶ BH4 bioavailability in the vasculature appears to be regulated by the following (Figure): (1) a de novo pathway using the rate-limiting enzyme GTP-cyclohydrolase I (GTPCH); (2) a salvage pathway from the synthetic pterin, sepiapterin, which is metabolized to BH4 by sepiapterin reductase (SR) and endothelial dihydrofolate reductase (DHFR); and (3) oxidative degradation of BH4 to dihydrobiopterin (BH2) that is inactive for eNOS cofactor function.^7,8 When BH4 levels are inadequate, the enzymatic reduction of molecular oxygen by eNOS is no longer coupled to L-arginine oxidation, resulting in generation of superoxide rather than NO. This phenomenon is referred as "eNOS uncoupling" and contributes to vascular oxidative stress and endothelial dysfunction.⁵

View larger version (14K):   Possible role of endothelial GTPCH in eNOS uncoupling and atherosclerosis. BH4 is synthesized de novo from guanosine triphosphate (GTP). The first and rate-limiting step in the de novo synthetic pathway is the enzyme GTP-cyclohydrolase I (GTPCH). Alternatively, BH4 synthesis can occur via . . . [Full Text of this Article]

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