Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs
Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs
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DOI：
10.1152/ajpheart.00176.2004
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发表时间：
2005-01-01
影响因子：
4.8
通讯作者：
Chiba, Y
中科院分区：
文献类型：
--
作者：
Li, W;Tanaka, K;Chiba, Y
据报道，血小板源性内皮细胞生长因子（PD-ECGF）也称为胸苷磷酸化酶（TP），具有血管生成活性并抑制细胞凋亡。本研究旨在确定 PD-ECGF/TP 是否可用于改善慢性心肌缺血。通过在近端左冠状动脉前降支 (LAD) 上放置 ameroid 收缩器，在 40 只杂种狗中造成心肌缺血。编码人 PD-ECGF/TP cDNA 的质粒载体（pCIhTP 组；n = 12）、空载体 pCI（pCI 组；n = 12）或盐水（盐水组；n = 12）在 ameroid 缩窄器植入后 3 周直接注射到 LAD 区域。在基线、ameroid 缩窄器植入后 3 周和治疗后 2 周使用 PET 检测心肌血流量。实验结束时，分离心脏进行生物学和组织学分析。在pCIhTP组中，转染的心脏强烈表达PD-ECGF/TP。 pCIhTP 组的梗塞面积小于 pCI 或盐水组。根据冯维勒布兰德因子、α-肌动蛋白平滑肌细胞和单链 DNA 的三重免疫组织化学染色，与对照组相比，pCIhTP 组凋亡心肌细胞的数量减少。与其他组相比，pCIhTP组促凋亡蛋白Bax的水平显着降低。血管性血友病因子和α-肌动蛋白平滑肌细胞的双重免疫组织化学染色表明，pCIhTP组发生了血管生成和动脉生成，并且与心肌血流和心肌功能的变化平行。我们得出结论，使用 PD-ECGF/TP 靶向心肌的遗传方法可有效缓解慢性心肌缺血。
Platelet-derived endothelial cell growth factor (PD-ECGF), also known as thymidine phosphorylase (TP), has been reported to possess angiogenic activity and to inhibit apoptosis. This study was performed to determine whether PD-ECGF/TP can be used to ameliorate chronic myocardial ischemia. Myocardial ischemia was created in 40 mongrel dogs by placement of an ameroid constrictor on the proximal left anterior descending coronary artery ( LAD). Plasmid vector encoding human PD-ECGF/TP cDNA (pCIhTP group; n = 12), empty vector pCI (pCI group; n = 12), or saline (Saline group; n = 12) was directly injected into the LAD territory 3 wk after ameroid constrictor implantation. Myocardial blood flow was detected using PET at baseline, 3 wk after ameroid constrictor implantation, and 2 wk after therapeutic treatment. At the end of the experiment, the hearts were isolated for biological and histological analysis. In the pCIhTP group, the transfected heart strongly expressed PD-ECGF/TP. The size of the infarct was smaller in the pCIhTP group than in the pCI or Saline group. The number of apoptotic myocardial cells was decreased in the pCIhTP group compared with the control groups based on triple immunohistochemical staining for von Willebrand factor, alpha-actin smooth muscle cells, and single-strand DNA. The level of proapoptotic protein Bax markedly decreased in the pCIhTP group compared with the other groups. Double immunohistochemical staining for von Willebrand factor and alpha-actin smooth muscle cells demonstrated that angiogenesis and arteriogenesis occurred, and paralleled the changes in myocardial blood flow and myocardial function in the pCIhTP group. We conclude that genetic approaches using PD-ECGF/TP to target the myocardium are effective for alleviating chronic myocardial ischemia.