Abstract 17098: Cardiac overexpression of GTP cyclohydrolase 1 attenuates cardiac remodeling after myocardial infarction by a neuronal nitric oxide synthase-mediated mechanism
Ge Z-D, Liu Y, Baumgardt SL, et al. Abstract 17098: Cardiac overexpression of GTP cyclohydrolase 1 attenuates cardiac remodeling after myocardial infarction by a neuronal nitric oxide synthase-mediated mechanism. Circulation. 2016;134(S1).
Introduction: Cardiac remodeling after myocardial infarction is associated with dysregulation of nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins. Emerging evidence suggests that GTP cyclohydrolase 1 (GCH1) regulates the function and expression of nitric oxide synthase and sarcoplasmic reticulum Ca2+ handling proteins.
Hypothesis: We hypothesized that cardiac overexpression of GCH1 will benefit postinfarct cardiac remodeling.
Methods: Myocardial infarction was produced in transgenic mice with cardiomyocyte-specific overexpression of human GCH1 and in control C57BL/6 mice by ligating the left coronary artery. Sham control mice underwent the same procedures except coronary artery ligation. The left ventricular geometry and function were measured with echocardiography, in Masson’s trichrome-stained heart sections, or in isolated Langendorff-perfused hearts. The expression of GCH1, dimeric and monomeric nitric oxide synthases, sarcoplasmic reticulum Ca2+ handling proteins were determined by Western blot analyses.
Results: Compared with sham-operated mice, C57BL/6 mice undergoing coronary artery ligation showed significant decreases in cardiac GCH1 proteins (GCH1/GAPDH: 0.14±0.04 in infarction vs 0.50±0.08 in sham, n=6 mice/group, P<0.05), anterior wall thickness at end-diastole (0.67±0.04 mm vs. 0.92±0.07 mm, n=8-12 mice/group, P<0.05) and at end-systole, fractional shortening, +dP/dt, and the ratios of dimers/monomers of neuronal nitric oxide synthase, ryanodine receptors/GAPDH, and sarcoplasmic reticulum Ca2+ ATPase/GAPDH; and significant increases in infarct size, left ventricular internal diameters, and interstitial fibrosis 4 weeks after surgery. These adverse changes in the left ventricle were significantly attenuated in GCH1 overexpressing mice. Treatment of GCH1 overexpressing mice with 7-nitroindazole (an inhibitor for neuronal nitric oxide synthase) for 4 weeks blocked the beneficial effects of GCH1 overexpression on the heart after myocardial infarction.
Conclusions: Cardiac overexpression of GCH1 ameliorates postinfarct cardiac remodeling by elevating the dimerization of neuronal nitric oxide synthase and expression of sarcoplasmic reticulum Ca2+ handling proteins.