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

Abstract

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.