This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tarpey, M. M. Search for Related Content PubMed PubMed Citation Articles by Tarpey, M. M. Related Collections Pathophysiology Oxidant stress Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1519.)
© 2002 American Heart Association, Inc.

Editorials

Sepiapterin Treatment in Atherosclerosis

Margaret M. Tarpey

From the Department of Anesthesiology and the Center for Free Radical Biology, University of Alabama at Birmingham.

Correspondence to Margaret M. Tarpey, Department of Anesthesiology and the Center for Free Radical Biology, University of Alabama at Birmingham, 619 19th St South, Birmingham, AL 35233. E-mail margaret.tarpey@ccc.uab.edu

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

Tetrahydrobiopterin (BH₄) plays an important role in functional and metabolic cellular homeostasis, with additional effects on proliferation.,^1,2 immune responsiveness,^3,4 and neuronal activity.^5–7 Mutations in either de novo biosynthetic or regeneration (salvage) pathways result in BH₄ deficiency associated with diminished levels of seratonin and dopamine with progressive neurologic symptoms.^8,9 The phenotypic presentation of these synthetic mutations can be predicted in large part by the role of BH₄ as an obligatory cofactor in phenylalanine, tryptophan, and tyrosine hydroxylases (the rate-limiting enzymes for catecholamine and seratonin synthesis). The function of BH₄ in these aromatic amino acid hydroxylases involves redox-active donation of electrons and reductive enzyme activation and is associated with a tightly coupled system for regeneration of BH₄ from the oxidized dihydrobiopterin.^8,10

See page 1655

In addition to its role in the biosynthesis of monoamine neurotransmitters, BH₄ serves as an essential cofactor in all isoforms of nitric oxide synthases (NOS), with the Km for BH₄ for NOS several orders of magnitude lower than for the aromatic amino acid hydroxylases: NOS, 0.3 µmol/L vs 3 µmol/L for phenylalanine hydroxylase, 30 µmol/L for tyrosine hydroxylase and tryptophan hydroxylase, suggesting tight coupling of the cofactor with enzyme.⁸ However, the precise function(s) of BH₄ in NOS enzymatic activity is not as well defined as in the aromatic amino acid hydroxylase enzymes and may vary according to enzyme isoform. For endothelial NOS (eNOS), BH₄ has been reported to modulate the heme iron environment and stabilize and increase L-arginine binding, thus resulting in allosteric modulation of enzyme . . . [Full Text of this Article]

This article has been cited by other articles:

				L. Gao, Y.-F. Pung, J. Zhang, P. Chen, T. Wang, M. Li, M. Meza, L. Toro, and H. Cai Sepiapterin reductase regulation of endothelial tetrahydrobiopterin and nitric oxide bioavailability Am J Physiol Heart Circ Physiol, July 1, 2009; 297(1): H331 - H339. [Abstract] [Full Text] [PDF]

				A. G. Herman and S. Moncada Therapeutic potential of nitric oxide donors in the prevention and treatment of atherosclerosis Eur. Heart J., October 1, 2005; 26(19): 1945 - 1955. [Abstract] [Full Text] [PDF]

				M. S. Goligorsky Endothelial cell dysfunction: can't live with it, how to live without it Am J Physiol Renal Physiol, May 1, 2005; 288(5): F871 - F880. [Abstract] [Full Text] [PDF]

				M. d. C. P. Franco, Z. B. Fortes, E. H. Akamine, E. M. Kawamoto, C. Scavone, L. R. G. de Britto, M. N. Muscara, S. A. Teixeira, R. C. A. Tostes, M. H. C. Carvalho, et al. Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats J. Physiol., July 1, 2004; 558(1): 239 - 248. [Abstract] [Full Text] [PDF]

				S. Kawashima and M. Yokoyama Dysfunction of Endothelial Nitric Oxide Synthase and Atherosclerosis Arterioscler Thromb Vasc Biol, June 1, 2004; 24(6): 998 - 1005. [Abstract] [Full Text] [PDF]

				N. J. Alp, M. A. McAteer, J. Khoo, R. P. Choudhury, and K. M. Channon Increased Endothelial Tetrahydrobiopterin Synthesis by Targeted Transgenic GTP-Cyclohydrolase I Overexpression Reduces Endothelial Dysfunction and Atherosclerosis in ApoE-Knockout Mice Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 445 - 450. [Abstract] [Full Text]

				S. O. Hynes, L. A. Smith, D. M. Richardson, I. Kovesdi, T. O'Brien, and Z. S. Katusic In vivo expression and function of recombinant GTPCH I in the rabbit carotid artery Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H570 - H574. [Abstract] [Full Text] [PDF]

				E. R. Werner, A. C.F. Gorren, R. Heller, G. Werner-Felmayer, and B. Mayer Tetrahydrobiopterin and Nitric Oxide: Mechanistic and Pharmacological Aspects Experimental Biology and Medicine, December 1, 2003; 228(11): 1291 - 1302. [Abstract] [Full Text] [PDF]

				J.-S. Zheng, X.-Q. Yang, K. J. Lookingland, G. D. Fink, C. Hesslinger, G. Kapatos, I. Kovesdi, and A. F. Chen Gene Transfer of Human Guanosine 5'-Triphosphate Cyclohydrolase I Restores Vascular Tetrahydrobiopterin Level and Endothelial Function in Low Renin Hypertension Circulation, September 9, 2003; 108(10): 1238 - 1245. [Abstract] [Full Text] [PDF]