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Therapeutic angiogenesis using naked DNA expressing two isoforms of the hepatocyte growth factor in a porcine acute myocardial infarction model

^a Department of Thoracic and Cardiovascular Surgery, Cheju Halla General Hospital, Republic of Korea
^b Department of Thoracic and Cardiovascular Surgery, DongGuk University International Hospital, Republic of Korea
^c ViroMed Co., Ltd., Republic of Korea
^d Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
^e Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea
^f Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, 28, Yeongeon-dong, Jongno-gu, Seoul 110-744, Republic of Korea

Received 15 December 2007; received in revised form 14 May 2008; accepted 14 May 2008.

^_* Corresponding author. Tel.: +82 2 2072 3482; fax: +82 2 747 5245. (Email: kimkb{at}snu.ac.kr).

Objective: We evaluated the potency of therapeutic angiogenesis using intramyocardial injection of naked DNA expressing two isoforms of hepatocyte growth factor (pCK-HGF-X7) in a porcine myocardial infarction model. Methods: Four weeks after left anterior descending coronary artery ligation, 14 pigs were allocated to pCK-Null (negative control, n = 7) or pCK-HGF-X7 (n = 7) treatment groups. Gated myocardial single photon emission computed tomography was performed 4 and 8 weeks following coronary ligation. The effect of pCK-HGF-X7 on capillary density in the gene-injected myocardium was examined by histological analysis using alkaline phosphatase staining. Results: Segmental myocardial perfusion of the underperfused area (70%) from coronary ligation increased in the pCK-HGF-X7 group (p = 0.051), without significant differences in changes over time between the two groups (p = 0.54). Systolic wall thickening (p = 0.001), left ventricular end-diastolic (p = 0.045) and end-systolic volumes (p = 0.009), and left ventricular ejection fraction (p = 0.041) changed in both groups without significant differences in changes over time between the two groups. The increase in the left stoke volume was higher in the pCK-HGF-X7 group than in the pCK-Null group (p = 0.008). Histological analysis showed that capillary density was significantly higher in the pCK-HGF-X7 group than the pCK-Null group (p < 0.001). Conclusion: Intramyocardial injection of pCK-HGF-X7 induced significant angiogenesis at infarct-border zone, and increased the left ventricular stroke volume probably caused by reverse remodeling process.

Key Words: Gene therapy • Angiogenesis • Coronary artery disease