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

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