Non-Canonical Roles for Tetrahydrobiopterin in Cardiovascular Disease Pathogenesis

A molecule best known for helping blood vessels relax may also be driving heart damage through entirely different mechanisms inside heart muscle and immune cells. The cofactor tetrahydrobiopterin (BH4) is essential for producing nitric oxide, which keeps blood vessels healthy. Boosting BH4 in endothelial cells has long been seen as a promising way to prevent vascular disease. But recent evidence suggests BH4 also acts in cardiac myocytes and inflammatory cells, where it may influence cellular redox signalling, metabolism, and mitochondrial function—potentially in ways that worsen conditions such as ischaemia-reperfusion injury, heart attack, and heart failure. This project will use genetic mouse models that delete BH4 production specifically in these cell types, to untangle these conflicting roles. If successful, the work will clarify whether BH4 is friend or foe depending on where it acts. That distinction is critical for designing therapies that boost BH4’s beneficial effects in blood vessels without inadvertently amplifying its harmful effects in the heart. This is fundamental science: it will establish the mechanistic basis for cell-specific BH4 targeting, a necessary step before any clinical strategy can be developed.