Therapeutic angiogenesis in the ischemic canine heart induced by myocardial injection of naked complementary DNA plasmid encoding hepatocyte growth factor

Abstract

Objective: We investigated the efficacy of directly injecting a plasmid with complementary DNA encoding human hepatocyte growth factor into ischemic canine myocardium to induce angiogenesis. Methods: Four weeks after ligation of the left anterior descending coronary artery, 125 μg of a complementary DNA plasmid encoding the gene for either hepatocyte growth factor (n = 8) or LacZ (transfection control group, n = 8) was injected directly into the myocardium at the border between the normal tissue and the infarction. Eight other dogs were used as a sham control group. Regional thickening fraction, which indicated contractile function, and blood flow in the normal (circumflex branch territory) and ischemic areas were evaluated under dobutamine administration just before and 4 weeks after transfection. The animals were killed, and capillary numbers in both areas were assessed. These data in the ischemic area were evaluated as the percentage of those in the normal. Results: The number of myocardial capillaries in the ischemic area was successfully increased to approximately 140% of usual in the hepatocyte growth factor group, whereas no change was observed in the other groups (P = .0017 by analysis of variance). Furthermore, regional thickening fraction and blood flow in the ischemic area, which had deteriorated after coronary ligation, showed significant improvement in the hepatocyte growth factor group relative to the other groups (thickening fraction P < .0001 by analysis of variance, blood flow P = .0005 by analysis of variance). Conclusions: These results support the efficacy of the direct injection of plasmid complementary DNA encoding human hepatocyte growth factor to induce therapeutic angiogenesis in the ischemic myocardium.