Imperial College London
Faculty of Medicine, Hammersmith Campus
Dept. of Experimental Medicine and Toxicology
Du Cane Road,
London W12 0NN
Abstract: The integrity of the pulmonary vascular endothelium plays a key role in pulmonary vascular homeostasis. In particular, reduced endothelial-derived nitric oxide (NO) bioavailability is implicated in the pathogenesis of pulmonary hypertension. Recent studies in complementary murine genetic models provide clear evidence that tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), is a key determinant of NO production in pulmonary vasculature and that lack of BH4 leads to increased superoxide production. Congenital deficiency of BH4 in the mouse is associated with structural changes in pulmonary vessels from birth and pulmonary hypertension in the adult. Conversely, increased local production in vascular endothelium protects against hypoxia-induced pulmonary hypertension. The data suggest a possible therapeutic role for BH4 in the management of pulmonary hypertension.
Keywords: tretrahydrobiopterin; pulmonary hypertension; nitric oxide. Tetrahydrobiopterin Biosynthesis
Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases and nitric acid synthase (NOS). BH4 biosynthesis proceeds along a de novo pathway from guanosine triphosphate (GTP), via 7,8-dihydroneopterin triphosphate and 6-pyruvoyl-5,6,7,8-tetrahydropterin  (Figure 1). The committing and rate-limiting enzyme in BH4 synthesis is guanidine triphosphate cyclohydrolase I (GTPCH). Other enzymes in the synthetic pathway include 6-pyruvoyl-tetrahydropterin synthase (PTPS) and sapiapterin reductase (SR). PTPS can become rate-limiting in macrophages when GTPCH activity is up-regulated by cytokines . The intermediate
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