Cardiac‐specific overexpression of GTP cyclohydrolase 1 ameliorates cardiac dysfunction and remodeling after myocardial infarction

Abstract

GTP cyclohydrolase (GTPCH) 1 is the major determinant of concentrations of myocardial tetrahydrobiopterin, an essential cofactor for nitric oxide synthase. We examined whether cardiac‐specific overexpression of GTPCH 1 beneficially affected cardiac remodeling and function after myocardial infarction. Myocardial infarction was produced by ligating the left anterior descending coronary artery in GTPCH 1 overexpressing and wild‐type mice. Sham control mice underwent all surgical procedures without coronary artery ligation. Echocardiography was used to evaluate left ventricular (LV) dimensions and function. There were no significant differences in the thickness of LV anterior wall and posterior wall, internal diameters, and fractional shortening between sham‐operated GTPCH 1 and wild‐type groups. Four weeks after surgery, LV wall became thinner and LV was markedly dilated in wild‐type mice subjected to coronary ligation compared with those of wild‐type mice subjected to sham operation, but this effect was attenuated in GTPCH 1 overexpressing mice. Masson trichrome stained cross sections at mid‐ventricular level showed an enlarged LV cavity and increased collagen scar tissue in infarcted wild‐type hearts compared with infarcted GTPCH 1 overexpressing hearts. Infarct size expressed as a percentage of infarct circumference/total LV circumference was significantly smaller in infarcted GTPCH 1 overexpressing group than in infarcted wild‐type group (22.3±2.7% vs. 38.1±3.8%, n=8–10 mice/group, P<0.05). Myocardial interstitial fibrosis was significantly increased in infarcted wild‐type group compared with infarcted GTPCH 1 overexpressing group. These results demonstrate that cardiac‐specific overexpression of GTPCH 1 improves cardiac function and remodeling after myocardial infarction.