Abstract
Background: Emerging evidence suggests that GTP cyclohydrolase 1 (GTPCH) is critical for activity of nitric oxide synthase and sarcoplasmic reticulum Ca 2+ ATPase and myocardial relaxation in normal myocardium. We hypothesized that increased expression of GTPCH ameliorates cardiac dysfunction in streptozotocin (STZ)-induced diabetic cardiomyopathy. Methods: Transgenic mice with cardiomyocyte-specific overexpression of human GTPCH gene (GTPCH-Tg) and their wild-type littermates were injected with 50 mg/kg/day STZ (i.p.) for 5 consecutive days to induce diabetes or vehicle as control. Structure and function of the left ventricle were evaluated using echocardiography and in Langendorff-perfused hearts. Western blotting was used to measure expression of GTPCH and p38 mitogen-activated protein kinase (p38 MAPK). Cardiac biopterins were determined by HPLC. Results: Blood glucose concentrations were significantly increased in both GTPCH-Tg and wild-type mice 2 to 12 weeks after STZ injection. There were no significant differences in cardiac structure and function between vehicle-treated GTPCH-Tg and wild-type groups throughout the experiment. Twelve weeks after the injection, STZ-induced diabetes resulted in significant decreases in fractional shortening, the mitral E/A ratio, and ±dP/dt in wild-type mice (fractional shortening: 23±3% vs. 40±3% in vehicle; E/A: 1.36±0.10 vs. 1.87±0.12 in vehicle, n=10, P<0.05) but not GTPCH-Tg mice. The ratio of GTPCH/GAPDH was lower in STZ-treated wild-type than vehicle-treated wild-type mice (0.05±0.01 vs. 0.24±0.05 in vehicle, n=4, P<0.05). In contrast, the ratio of phosphorylated p38 MAPK/total p38 MAPK was significantly higher in STZ-treated wild-type than vehicle-treated wild-type mice. These negative effects of STZ-induced diabetes were abolished by GTPCH overexpression. Cardiac tetrahydrobiopterin levels were dramatically higher in GTPCH-Tg than wild-type mice in both vehicle- and STZ-treated groups. Conclusions: Decreased GTPCH contributes to cardiac dysfunction in STZ-induced diabetic cardiomyopathy. Cardiac overexpression of GTPCH improves cardiac function in diabetic cardiomyopathy by decreasing activation of p38 MAPK and increasing cardiac tetrahydrobioptein levels.
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