Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury.

The cofactor tetrahydrobiopterin (BH 4 ) is a critical regulator of nitric oxide synthase (NOS) function and redox signaling, with reduced BH 4 implicated in multiple cardiovascular disease states. In the myocardium, augmentation of BH 4 levels can impact on cardiomyocyte function, preventing hypertrophy and heart failure. However, the specific role of endothelial cell BH 4 biosynthesis in the coronary circulation and its role in cardiac function and the response to ischemia has yet to be elucidated. Endothelial cell-specific Gch1 knockout mice were generated by crossing Gch1 fl/fl with Tie2cre mice, generating Gch1 fl/fl Tie2cre mice and littermate controls. GTP cyclohydrolase protein and BH 4 levels were reduced in heart tissues from Gch1 fl/fl Tie2cre mice, localized to endothelial cells, with normal cardiomyocyte BH 4 . Deficiency in coronary endothelial cell BH 4 led to NOS uncoupling, decreased NO bioactivity, and increased superoxide and hydrogen peroxide productions in the hearts of Gch1 fl/fl Tie2cre mice. Under physiological conditions, loss of endothelial cell-specific BH 4 led to mild cardiac hypertrophy in Gch1 fl/fl Tie2cre hearts. Endothelial cell BH 4 loss was also associated with increased neuronal NOS protein, loss of endothelial NOS protein, and increased phospholamban phosphorylation at serine-17 in cardiomyocytes. Loss of cardiac endothelial cell BH 4 led to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia-reperfusion injury. Taken together, these studies reveal a specific role for endothelial cell Gch1 /BH 4 biosynthesis in cardiac function and the response to cardiac ischemia-reperfusion injury. Targeting endothelial cell Gch1 and BH 4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction and ischemia-reperfusion injury. NEW & NOTEWORTHY We demonstrate a critical role for endothelial cell Gch1 /BH 4 biosynthesis in coronary vascular function and cardiac function. Loss of cardiac endothelial cell BH 4 leads to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia/reperfusion injury. Targeting endothelial cell Gch1 and BH 4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction, ischemia injury, and heart failure.