Long-term effect of gene therapy for chronic ischemic myocardium using platelet-derived endothelial cell growth factor in dogs
Long-term effect of gene therapy for chronic ischemic myocardium using platelet-derived endothelial cell growth factor in dogs
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DOI：
10.1002/jgm.1156
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发表时间：
2008-04-01
影响因子：
3.5
通讯作者：
Ihaya, Akio
中科院分区：
文献类型：
--
作者：
Li, Wei;Tanaka, Kuniyoshi;Ihaya, Akio
背景我们先前报道了血小板源性内皮细胞生长因子（PD-ECGF）基因治疗慢性缺血心肌2周的疗效。然而，长期的影响和安全性，使用该基因还没有report.Methods慢性心肌缺血24只狗通过狭窄的左前降支冠状动脉（LAD）的起源使用ameroid收缩。两周后，将PD-ECGF基因、LacZ基因或生理盐水直接输注到LAD区域的心肌中。分别于缺血前、基因注射前即刻、注射后6个月检测心肌血容量和心肌功能，并进行组织学和分子生物学检查。Ameroid植入后，三组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，并在检查期间保持较高水平的功能。组织学分析表明，PD-ECGF基因治疗后发生血管生成和动脉生成。PD-ECGF治疗组促凋亡蛋白、活性caspase-3和Bax的表达减少，凋亡心肌细胞数量减少。组织学检查表明，没有异常的组织学变化或肿瘤被发现在任何organs.Conclusions缺血心肌基因靶向使用PD-ECGF产生长期改善心功能，引起血管生成，动脉生成和抑制细胞凋亡，但没有诱导肿瘤在远程器官，可能是一个有前途的治疗。版权所有（c）2008约翰威利父子有限公司。
Background We previously reported the 2-week benefits of platelet-derived endothelial cell growth factor (PD-ECGF) gene therapy in chronically ischernic myocardium. However, the long-term effects and safety using this gene have not been reported.Methods 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.Results 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.Conclusions 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. Copyright (c) 2008 John Wiley & Sons, Ltd.