Cardiomyocyte GTP Cyclohydrolase 1 and Tetrahydrobiopterin Increase NOS1 Activity and Accelerate Myocardial Relaxation

• DOI: 10.1161/circresaha.112.274464
• Publication Date: 2012-07-14T09:30:33Z
• Authors: Ricardo Carnicer; Ashley B. Hale; Silvia Suffredini; Xing Liu; Svetlana Reilly; Mei Hua Zhang; Nicoletta C. Surdo; Jennifer K. Bendall; Mark J. Crabtree; Gregory B.S. Lim; Nicholas J. Alp; Keith M. Channon; Barbara Casadei
• Keywords: Biopterin; NOS1; GTP cyclohydrolase I

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthases (NOS). Oral BH4 supplementation preserves cardiac function in animal models disease; however, the mechanisms underlying these findings are not completely understood.To study effect myocardial transgenic overexpression rate-limiting enzyme biosynthesis, GTP cyclohydrolase 1 (GCH1), on NOS activity, function, and Ca2+ handling.GCH1overexpression significantly increased biopterins level left ventricular (LV) myocytes but nonmyocyte component LV myocardium or plasma. The ratio between its oxidized products was lower mGCH1-Tg, indicating that a large proportion biopterin pool oxidized; nevertheless, NOS1 activity superoxide release reduced. Isolated hearts field-stimulated (3 Hz, 35°C) overexpressing GCH1 showed faster relaxation PKA-mediated increase PLB Ser16 phosphorylated fraction rate decay [Ca2+]i transient. RyR2 S-nitrosylation diastolic leak were larger mGCH1-Tg ICa density lower; nevertheless amplitude transient contraction did differ genotypes, because SR fractional myocytes. Xanthine oxidoreductase inhibition abolished difference production affect either group. By contrast, differences density, phosphorylation, decay, genotypes.Myocardial intracellular limiting factor for constitutive SERCA2A healthy myocardium. Our suggest may be valuable target treatment dysfunction.