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Review
. 2009 Jan;30(1):48-54.
doi: 10.1016/j.tips.2008.10.003. Epub 2008 Nov 29.

Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects

Zvonimir S Katusic  1 , Livius V d'Uscio, Karl A Nath
Affiliations
Review

Vascular protection by tetrahydrobiopterin: progress and therapeutic prospects

Zvonimir S Katusic et al. Trends Pharmacol Sci. 2009 Jan.

Abstract

Tetrahydrobiopterin (BH4) is an essential cofactor required for the activity of endothelial nitric oxide (NO) synthase. Suboptimal concentrations of BH4 in the endothelium reduce the biosynthesis of NO, thus contributing to the pathogenesis of vascular endothelial dysfunction. Supplementation with exogenous BH4 or therapeutic approaches that increase endogenous amounts of BH4 can reduce or reverse endothelial dysfunction by restoring production of NO. Improvements in formulations of BH4 for oral delivery have stimulated clinical trials that test the efficacy of BH4 in the treatment of systemic hypertension, peripheral arterial disease, coronary artery disease, pulmonary arterial hypertension, and sickle cell disease. This review discusses ongoing progress in the translation of knowledge, accumulated in preclinical studies, into the clinical application of BH4 in the treatment of vascular diseases. This review also addresses the emerging roles of BH4 in the regulation of endothelial function and their therapeutic implications.

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Figures

Figure 1
Figure 1
Biosynthesis of BH4. GTP cyclohydrolase I (GTP-CH) is the rate-limiting enzyme in the de novo synthetic pathway of BH4. Pyruvoyl tetrahydroptrein synthase (PTPS) and sepiapterin reductase (SR) are two additional enzymes required for the final production of BH4. BH4 can also be synthesized from sepiapterin by the so-called “salvage pathway”. BH4 oxidized by peroxynitrite to BH2 can be recycled back to BH4 by activity of dihydrofolate reductase (DHFR). Neopterin is a stable side-product of BH4 that may serve as an indicator of elevated GTPCH activity.
Figure 2
Figure 2
Schematic representation of endothelial nitric oxide synthase (eNOS) uncoupling. During uncoupling, biosynthesis of nitric oxide (NO) is uncoupled from consumption of NADPH and electron flow is directed towards formation of superoxide anion (O2.−) and hydrogen peroxide (H2O2). Subsequent reaction between superoxide anion and NO generates peroxynitrite anion (ONOO−). Suboptimal concentrations of BH4 (↓).
See this image and copyright information in PMC

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