Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy
Angiogenic and antifibrotic actions of hepatocyte growth factor improve cardiac dysfunction in porcine ischemic cardiomyopathy
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DOI：
10.1038/sj.gt.3302740
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发表时间：
2006-08-01
期刊：
影响因子：
5.1
通讯作者：
Morishita, R.
中科院分区：
文献类型：
--
作者：
Azuma, J.;Taniyama, Y.;Morishita, R.
缺血性心肌病的心功能损害被认为是由于血流量减少和胶原合成增加。因此，通过生长因子直接改变它们的方法可能为缺血性心肌病开辟一个新的治疗概念。从这个观点来看，肝细胞生长因子（HGF）是一种独特的生长因子，具有血管生成和抗纤维化作用。因此，我们研究了使用HGF质粒DNA进行缺血性心肌病基因治疗的可行性。用NOGA系统将人HGF质粒DNA以0.4或4 mg的剂量注射到由Ameroid缩窄器诱发的猪缺血心肌中。注射后1个月，HGF组缺血面积明显缩小，缺血区毛细血管密度和局部心肌灌注明显增加（P < 0.01）。相比之下，与对照组相比，在HGF组中观察到纤维化面积的显著减少，与胶原I、III和TGF-β合成的显著减少相关（P < 0.01）。与对照组比较，HGF 4 mg组心功能明显改善（P < 0.05）。总体而言，本体内实验证明，在缺血性心肌病中心肌内注射人HGF质粒DNA通过增加血流量和减少纤维化而导致心脏功能的显著改善。这些有利的结果表明，使用HGF基因转移治疗缺血性心脏病患者的潜在效用。目前，使用人HGF质粒DNA的I期研究正在进行中，以测试这一概念的有效性。
Impairment of cardiac function in ischemic cardiomyopathy has been postulated to be due to the decrease in blood flow and increase in collagen synthesis. Therefore, an approach to alter them directly by means of a growth factor may open up a new therapeutic concept in ischemic cardiomyopathy. From this viewpoint, hepatocyte growth factor (HGF) is a unique growth factor with angiogenic and antifibrotic effects. Thus, we examined the feasibility of gene therapy using HGF plasmid DNA for ischemic cardiomyopathy. Human HGF plasmid DNA at a dose of 0.4 or 4 mg was injected into ischemic myocardium of pigs induced by ameroid constrictor with the NOGA system. At 1 month after injection, the ischemic area was significantly reduced in the HGF group, accompanied by a significant increase in capillary density and regional myocardial perfusion in the ischemic area (P < 0.01). In contrast, a significant decrease in fibrotic area was observed in the HGF group, associated with a significant decrease in collagen I, III and TGF-beta synthesis as compared to the control group (P < 0.01). Consistently, cardiac function was significantly improved in the 4 mg HGF group as compared to the control group (P < 0.05). Overall, the present in vivo experiments demonstrated that intramyocardial injection of human HGF plasmid DNA in ischemic cardiomyopathy resulted in a significant improvement in cardiac function through an increase in blood flow and decrease in fibrosis. These favorable outcomes suggest potential utility to treat patients with ischemic heart disease using HGF gene transfer. Currently, a phase I study using human HGF plasmid DNA is ongoing to test the validity of this concept.