Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer: comparison of low-, medium- and high-dose groups

Despite advances in surgical and reperfusion therapy, there is no effective therapy currently exists to prevent the progressive decline in cardiac function following myocardial infarction. Hepatocyte growth factor has potent angiogenic and anti-apoptotic activities. The aim of this study was to investigate the therapeutic effect and dose–effect relationship on postinfarction heart failure with different doses of adenovirus-mediated human hepatocyte growth factor (Ad5-HGF) transference in swine models. Totally twenty swine were randomly divided into four groups: (a) control group (null- Ad5, 1 ml); (b) low-dose group (1 × 109 Pfu/ml Ad5-HGF, 1 ml); (c) medium-dose group (5 × 109 Pfu/ml Ad5-HGF, 1 ml); (d) high-dose group (1 × 1010 Pfu/ml Ad5-HGF, 1 ml). Four weeks after left anterior descending coronary artery (LAD) ligation, different doses of Ad5-HGF were transferred in three therapeutic groups via right coronary artery. Four and seven weeks after LAD ligation, gate cardiac perfusion imaging was performed to evaluate cardiac perfusion and left ventricular ejection fraction (LVEF). Seven weeks after surgery, the apoptotic index of cardiocyte was observed by TUNEL, the expression of Bcl-2, Bax, α-SMA and Factor VIII in the border zones were evaluated by immunohistochemistry, respectively. Four weeks after myocardial infarction, no significant difference was observed among four groups. Three weeks after Ad5-HGF transfer, the improvement of cardiac perfusion and LVEF was obviously observed, especially after 1 × 1010 Pfu Ad5-HGF transfer. TUNEL assay showed that 5 × 109 Pfu and 1 × 1010 Pfu Ad5-HGF treatment had a obvious reduction in the apoptotic index compared with the null-Ad5 group, especially after 1 × 1010 Pfu Ad5-HGF treatment. The expression of Bcl-2 protein was increased and the expression of Bax protein was inhibited in the 5 × 109 Pfu and 1 × 1010 Pfu Ad5-HGF groups compared with the null-Ad5 group. The vessel density of Factor VIII+ and α-SMA+ was increased in Ad5-HGF groups compared with the null-Ad5 group. There were no significant differences in angiogenesis, reducing apoptosis and ameliorating heart function between the 1 × 109 Pfu Ad5-HGF group and the null-Ad5 group. Although no statistical difference was observed between 1 × 1010 Pfu and 5 × 109 Pfu Ad5-HGF groups, the cardiac protective effects of 1 × 1010 Pfu Ad5-HGF treatment were greater than 5 × 109 Pfu Ad5-HGF treatment. Different doses of Ad5-HGF injected via noninfarct-related artery could induce angiogenesis, reduce apoptosis and ameliorate heart function, and the cardiac protective effects of 1 × 1010 Pfu Ad5-HGF is of most significance.