View article

The redox co-factor tetrahydrobiopterin (BH₄) regulates nitric oxide (NO) and reactive oxygen species (ROS) production by endothelial NOS (eNOS) and is an important redox-dependent signalling molecule in the endothelium. Loss of endothelial BH₄ is observed in cardiovascular disease (CVD) states and results in decreased NO and increased superoxide (O₂^-) generation via eNOS uncoupling. Genetic mouse models of augmented endothelial BH₄ synthesis have shown proof of concept that endothelial BH₄ can alter CVD pathogenesis. However, clinical trials of BH₄ therapy in vascular disease have been limited by systemic oxidation, highlighting the need to explore the wider roles of BH₄ to find novel therapeutic targets. In this study, we aimed to elucidate the effects of BH₄ deficiency on mitochondrial function and bioenergetics using targeted knockdown of the BH₄ synthetic enzyme, GTP Cyclohydrolase I …