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Updated: Jun 21, 2026
Gene Transfer for Ischemic Heart Failure in a Preclinical Model
Published on: May 15, 2011
Improvement of heart function in postinfarct heart failure swine models after hepatocyte growth factor gene transfer:
Zhi-jian Yang1, Bo Chen, Zhang Sheng
1Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210029, Nanjing, China. enzhijia@yahoo.com.cn
Insights
Hepatocyte growth factor (HGF) gene therapy shows promise for treating post-myocardial infarction heart failure. High-dose adenovirus-mediated HGF (Ad(5)-HGF) significantly improved cardiac function, reduced cell death, and promoted blood vessel growth in swine models.
Area of Science:
- Cardiovascular Research
- Gene Therapy
- Regenerative Medicine
Background:
- Myocardial infarction (MI) leads to progressive heart failure despite current therapies.
- Hepatocyte growth factor (HGF) exhibits angiogenic and anti-apoptotic properties, suggesting therapeutic potential.
Purpose of the Study:
- To evaluate the therapeutic efficacy and dose-response relationship of adenovirus-mediated human HGF (Ad(5)-HGF) in a swine model of post-infarction heart failure.
Main Methods:
- Swine underwent LAD ligation followed by administration of varying doses of Ad(5)-HGF or a control vector.
- Cardiac function (perfusion, LVEF) was assessed using imaging.
- Cardiomyocyte apoptosis, and expression of Bcl-2, Bax, alpha-SMA, and Factor VIII were evaluated via TUNEL assay and immunohistochemistry.
Main Results:
- High-dose Ad(5)-HGF (1 x 10(10) Pfu/ml) significantly improved cardiac perfusion and LVEF compared to controls.
- Ad(5)-HGF treatment reduced cardiomyocyte apoptosis and increased Bcl-2 expression while decreasing Bax expression.
- Increased vessel density (Factor VIII+, alpha-SMA+) was observed in Ad(5)-HGF treated groups, with the highest dose showing the most significant effects.
Conclusions:
- Adenovirus-mediated HGF gene transfer effectively induces angiogenesis, reduces apoptosis, and ameliorates cardiac function post-myocardial infarction.
- A dose-dependent protective effect was observed, with the highest dose of Ad(5)-HGF demonstrating the most significant therapeutic benefits.
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 (Ad(5)-HGF) transference in swine models. Totally twenty swine were randomly divided into four groups: (a) control group (null- Ad(5), 1 ml); (b) low-dose group (1 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (c) medium-dose group (5 x 10(9) Pfu/ml Ad(5)-HGF, 1 ml); (d) high-dose group (1 x 10(10) Pfu/ml Ad(5)-HGF, 1 ml). Four weeks after left anterior descending coronary artery (LAD) ligation, different doses of Ad(5)-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, alpha-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 Ad(5)-HGF transfer, the improvement of cardiac perfusion and LVEF was obviously observed, especially after 1 x 10(10) Pfu Ad(5)-HGF transfer. TUNEL assay showed that 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF treatment had a obvious reduction in the apoptotic index compared with the null-Ad(5) group, especially after 1 x 10(10) Pfu Ad(5)-HGF treatment. The expression of Bcl-2 protein was increased and the expression of Bax protein was inhibited in the 5 x 10(9) Pfu and 1 x 10(10) Pfu Ad(5)-HGF groups compared with the null-Ad(5) group. The vessel density of Factor VIII(+) and alpha-SMA(+) was increased in Ad(5)-HGF groups compared with the null-Ad(5) group. There were no significant differences in angiogenesis, reducing apoptosis and ameliorating heart function between the 1 x 10(9) Pfu Ad(5)-HGF group and the null-Ad(5) group. Although no statistical difference was observed between 1 x 10(10) Pfu and 5 x 10(9) Pfu Ad(5)-HGF groups, the cardiac protective effects of 1 x 10(10) Pfu Ad(5)-HGF treatment were greater than 5 x 10(9) Pfu Ad(5)-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 x 10(10) Pfu Ad5-HGF is of most significance.
