Li Wei, Tanaka Kuniyoshi, Morioka Koichi, Takamori Atsushi, Handa Mitsuteru, Yamada Narihisa, Ihaya Akio
Second Department of Surgery, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
J Gene Med. 2008 Apr;10(4):412-20. doi: 10.1002/jgm.1156.
We previously reported the 2-week benefits of platelet-derived endothelial cell growth factor (PD-ECGF) gene therapy in chronically ischemic myocardium. However, the long-term effects and safety using this gene have not been reported.
Chronic myocardial ischemia was created in 24 dogs by stenosing the origin of the left anterior descending coronary artery (LAD) using an ameroid constrictor. Two weeks later, the PD-ECGF gene, the LacZ gene, or saline was infused directly into the myocardium in the LAD area. The myocardial blood volume and myocardial function were examined prior to ischemia, immediately before gene injection, and for 6 months following injection, and then the organs were harvested for histological and molecular examination.
PD-ECGF gene treatment significantly attenuated endocardial infarction at 6 months. Myocardial blood volume and myocardial function decreased in all three groups after ameroid implantation, but recovered after 2 weeks in the PD-ECGF-treated group, and maintained a higher level of function during the examination period. Histological analysis demonstrated that angiogenesis and arteriogenesis occurred after PD-ECGF gene treatment. There was a decreased expression of the pro-apoptotic proteins, active caspase-3 and Bax, and the number of apoptotic myocardial cells was lower in the PD-ECGF-treated group. Histological examination demonstrated that no abnormal histological changes or neoplasms were found in any organs.
We conclude that gene targeting of ischemic myocardium using PD-ECGF generated long-term improvement in cardiac function by causing angiogenesis, arteriogenesis and inhibiting apoptosis, but did not induce neoplasms in the remote organs, and may be a promising therapy.
我们之前报道了血小板衍生内皮细胞生长因子（PD-ECGF）基因疗法对慢性缺血心肌的两周疗效。然而，使用该基因的长期效果和安全性尚未见报道。
通过用阿霉素环缩器缩窄左前降支冠状动脉（LAD）起始部，在24只犬中制造慢性心肌缺血。两周后，将PD-ECGF基因、LacZ基因或生理盐水直接注入LAD区域的心肌。在缺血前、基因注射前即刻以及注射后6个月检测心肌血容量和心肌功能，然后取器官进行组织学和分子检查。
PD-ECGF基因治疗在6个月时显著减轻心内膜梗死。阿霉素植入后，三组的心肌血容量和心肌功能均下降，但PD-ECGF治疗组在2周后恢复，并在检查期间维持较高的功能水平。组织学分析表明，PD-ECGF基因治疗后发生了血管生成和动脉生成。促凋亡蛋白活性半胱天冬酶-3和Bax的表达降低，PD-ECGF治疗组凋亡心肌细胞数量较少。组织学检查表明，任何器官均未发现异常组织学变化或肿瘤。
我们得出结论，使用PD-ECGF对缺血心肌进行基因靶向治疗可通过促进血管生成、动脉生成和抑制凋亡长期改善心脏功能，但不会在远处器官诱发肿瘤，可能是一种有前景的治疗方法。
