GTP cyclohydrolase 1 (GCH1) and its product
tetrahydrobiopterin play crucial roles in cardiovascular health and disease, yet the exact regulation and role of GCH1 in adverse cardiac remodeling after
myocardial infarction are still enigmatic. Here we report that cardiac GCH1 is degraded in remodeled hearts after
myocardial infarction, concomitant with increases in the thickness of interventricular septum, interstitial
fibrosis, and phosphorylated
p38 mitogen-activated protein kinase and decreases in left ventricular anterior wall thickness, cardiac contractility,
tetrahydrobiopterin, the dimers of
nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and the expression of sarcoplasmic reticulum Ca2+ handling
proteins. Intriguingly, transgenic overexpression of GCH1 in cardiomyocytes reduces the thickness of interventricular septum and interstitial
fibrosis and increases anterior wall thickness and cardiac contractility after
infarction. Moreover, we show that GCH1 overexpression decreases phosphorylated
p38 mitogen-activated protein kinase and elevates
tetrahydrobiopterin levels, the dimerization and phosphorylation of
neuronal nitric oxide synthase, sarcoplasmic reticulum Ca2+ release, and sarcoplasmic reticulum Ca2+ handling
proteins in post-
infarction remodeled hearts. Our results indicate that the pivotal role of GCH1 overexpression in post-
infarction cardiac remodeling is attributable to preservation of
neuronal nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling
proteins, and identify a new therapeutic target for cardiac remodeling after
infarction.