Nandi, Manasi; (2004) Tetrahydrobiopterin: Nitric Oxide and Pulmonary Vascular Control. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

GTP-cyclohydrolase 1 (GTP-CH1) catalyses the first and rate limiting step for the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase (NOS). NOS, once active, generates nitric oxide (NO) an essential mediator of normal vascular tone and function. Suboptimal levels of BH4 may render NOS inefficient and may additionally result in the generation of deleterious superoxide anions (O2-). GTP-CH1 is itself inhibited by BH4, an effect mediated via the protein GTP-CH1 Feedback Regulatory Protein (GFRP). There is mounting evidence correlating a dysfunction of the BH4/NOS pathway with the vascular endothelial dysfunction observed e.g. atherosclerosis, but little evidence exists associating a dysfunction of this pathway with pulmonary hypertension (PH). I have shown that GTP-CH1 protein expression is developmentally regulated in the porcine lung in the first few weeks of life, correlating with functional effects of supplemented BH4 on isolated pulmonary arteries. GTP-CH1 protein expression is unchanged in animals exposed to hypobaric exposure (a model of persistent pulmonary hypertension of the newborn (PPHN)) when compared to their age matched controls and GTP-CH1 localisation appeared unchanged both developmentally and in PPHN. Thus GTP-CH1 levels do not appear to be implicated in the profound endothelial dysfunction observed in animals with PPHN. However, studies performed on the GTP-CH1 deficient mouse mutant (hph-1) indicate that these mice exhibit the structural characteristics of a pulmonary hypertensive phenotype when compared to the C57BL/6xCBA wild types. Finally, GFRP over expression in isolated endothelial cells attenuates inducible NOS (iNOS) mediated NO generation following cytokine stimulation, an effect likely to be mediated via direct inhibition of BH4 biosynthesis. In summary, these studies have demonstrated that regulation of BH4 via GTP-CH1 or GFRP, affects the NOS pathway both in vitro and in vivo and that sub optimal levels of BH4 may contribute towards the development of PH.

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