The regulation of vascular tetrahydrobiopterin bioavailability

6R l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) is an essential cofactor for several enzymes including phenylalanine hydroxylase and the nitric oxide synthases (NOS). Oral supplementation of BH4 has been successfully employed to treat subsets of patients with hyperphenylalaninaemia. More recently, research efforts have focussed on understanding whether BH4 supplementation may also be efficacious in cardiovascular disorders that are underpinned by reduced nitric oxide bioavailability. Whilst numerous preclinical and clinical studies have demonstrated a positive association between enhanced BH4 and vascular function, the efficacy of orally administered BH4 in human cardiovascular disease remains unclear. Furthermore, interventions that limit BH4 bioavailability may provide benefit in diseases where nitric oxide over production contributes to pathology. This review describes the pathways involved in BH4 bio-regulation and discusses other endogenous mechanisms that could be harnessed therapeutically to manipulate vascular BH4 levels.

Tetrahydrobiopterin (BH4) bioavailability is an important regulator of nitric oxide synthase (NOS) functionality and represents a tractable therapeutic target for the treatment of diseases characterised by alterations in NO production. Under conditions of reduced BH4 bioavailability, eNOS can become ‘uncoupled’ and generate reactive oxygen species, further propagating vascular dysfunction. BH4 levels could be enhanced by: 1) exogenous BH4 administration, which has shown conflicting efficacy in clinical trials; 2) pharmacological activation of the GCH1–GFRP complex, 3) enhancing the reduction of endogenous BH2 to BH4 (salvage pathway) and 4) attenuating the oxidation of BH4. Conversely, a rise in GCH1 activity and BH4 levels occurs under proinflammatory conditions. This rise in BH4 is believed to support iNOS dimerisation and activity promoting the generation of high concentrations of NO, which can lead to circulatory collapse in septic shock. Under these conditions the rise in BH4 could be attenuated by using pharmacological inhibitors of the GCH1–GFRP complex or agents that prevent BH4 binding to iNOS.Figure optionsDownload high-quality image (221 K)Download as PowerPoint slide