Endothelial cell-specific roles for tetrahydrobiopterin in myocardial function, cardiac hypertrophy, and response to myocardial ischemia-reperfusion injury.
Surawee ChuaiphichaiSandy M ChuRicardo CarnicerMatthew KellyJenifer K BendallJillian N SimonGillian DouglasMark J CrabtreeBarbara CasadeiKeith M ChannonPublished in: American journal of physiology. Heart and circulatory physiology (2023)
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.
Keyphrases
- endothelial cells
- ischemia reperfusion injury
- high glucose
- left ventricular
- nitric oxide synthase
- heart failure
- oxidative stress
- hydrogen peroxide
- coronary artery disease
- cardiovascular disease
- vascular endothelial growth factor
- coronary artery
- nitric oxide
- acute myocardial infarction
- gene expression
- type diabetes
- high fat diet induced
- metabolic syndrome
- cell wall
- binding protein
- small molecule
- cancer therapy
- skeletal muscle
- genome wide
- amino acid
- acute coronary syndrome
- insulin resistance
- adipose tissue
- blood brain barrier
- replacement therapy
- transcatheter aortic valve replacement
- combination therapy
- protein kinase
- smoking cessation