Endothelial Cell-Specific Roles for Tetrahydrobiopterin in Myocardial Function, Cardiac Hypertrophy and Response to Myocardial Ischemia-Reperfusion Injury.
Chuaiphichai S., Chu SM., Carnicer R., Kelly M., Bendall JK., Simon JN., Douglas G., Crabtree MJ., Casadei B., Channon KM.
INTRODUCTION: The cofactor tetrahydrobiopterin (BH4) is a critical regulator of nitric oxide synthase (NOS) function and redox signalling, with reduced BH4 implicated in multiple cardiovascular disease states. In the myocardium, augmentation of BH4 levels can impact on cardiomyocyte function, preventing hypertrophy and heart failure. However, the specific role of endothelial cell BH4 biosynthesis in the coronary circulation and its role in cardiac function and the response to ischaemia has yet to be elucidated. METHODS/RESULTS: Endothelial cell specific Gch1 knock out mice were generated by crossing Gch1fl/f with Tie2cre mice, generating Gch1fl/flTie2cre mice and littermate controls. GTPCH protein and BH4 levels were reduced in heart tissues from Gch1fl/flTie2cre mice, localized to endothelial cells, with normal cardiomyocyte BH4. Deficiency in coronary endothelial cell BH4 led to NOS uncoupling, decreased NO bioactivity, and increased superoxide and hydrogen peroxide production in hearts of Gch1fl/flTie2cre mice. Under physiological condition, loss of endothelial cell-specific BH4 led to mild cardiac hypertrophy in Gch1fl/flTie2cre hearts. Endothelial cell BH4 loss was also associated with increased nNOS protein, loss of eNOS protein and increased phospholamban phosphorylation at Ser17 in cardiomyocytes. Loss of cardiac endothelial cell BH4 led to coronary vascular dysfunction, reduced functional recovery and increased myocardial infarct size following ischemia/reperfusion injury. CONCLUSION: Taken together, these studies reveal a specific role for endothelial cell Gch1/BH4 biosynthesis in cardiac function and the response to cardiac ischemia/reperfusion injury. Targeting endothelial cell Gch1 and BH4 biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction and ischaemia-reperfusion injury.