Hypoxia-inducible VEGF gene delivery to ischemic myocardium using water-soluble lipopolymer
Hypoxia-inducible VEGF gene delivery to ischemic myocardium using water-soluble lipopolymer
复制标题
DOI：
10.1038/sj.gt.3302034
复制
发表时间：
2003-09-01
期刊：
影响因子：
5.1
通讯作者：
Kim, SW
中科院分区：
文献类型：
--
作者：
Lee, M;Rentz, J;Kim, SW
血管内皮生长因子（VEGF）基因治疗性血管生成是一种新的治疗心血管疾病的潜在方法。然而，不受调节的VEGF介导的血管生成具有促进肿瘤生长、加速糖尿病增殖性视网膜病变和促进动脉粥样硬化斑块破裂的潜力。为了安全和有效，VEGF的基因治疗必须受到监管。为了限制病理性血管生成的风险，我们开发了一种缺氧诱导的VEGF基因治疗系统，使用促红细胞生成素（Epo）增强剂和水溶性脂聚合物（WSLP）。将Epo增强子插入猴病毒40（SV 40）启动子上游或pSV-VEGF的poly（A）信号下游，构建了pEpo-SV-VEGF或pSV-VEGF-Epo。体外转染表明，pEpo-SV-VEGF而不是pSV-VEGF-Epo能诱导缺氧细胞中VEGF的表达。此外，从Epo-SV-VEGF转染和缺氧孵育的细胞产生的VEGF蛋白能够增强内皮细胞的增殖。注射pEpo-SV-VEGF/ WSLP复合物显示，与正常心肌相比，VEGF在缺血心肌中的表达被诱导。因此，pEpo-SV-VEGF/WSLP系统具有局部诱导VEGF表达和WSLP低细胞毒性的特点，可能有助于缺血性心脏病的治疗。
Therapeutic angiogenesis with gene encoding vascular endothelial growth factor (VEGF) is a new potential treatment in cardiovascular disease. However, unregulated VEGF-mediated angiogenesis has the potential to promote tumor growth, accelerate diabetic proliferative retinopathy, and promote rupture of atherosclerotic plaque. To be safe and effective, gene therapy with VEGF must be regulated. To limit the risk of pathological angiogenesis, we developed a hypoxia-inducible VEGF gene therapy system using the erythropoietin (Epo) enhancer and water-soluble lipopolymer (WSLP). pEpo-SV-VEGF or pSV-VEGF-Epo was constructed by insertion of the Epo enhancer upstream of the Simian Virus 40 (SV40) promoter or downstream of the poly(A) signal of pSV-VEGF In vitro transfection showed that pEpo-SV-VEGF, not pSV-VEGF-Epo, induced the VEGF expression in hypoxic cells. In addition, the VEGF protein, which was produced from the Epo-SV-VEGF-transfected and hypoxia-incubated cells, was able to enhance the proliferation of the endothelial cells. Injection of the pEpo-SV-VEGF/ WSLP complex showed that the expression of VEGF was induced in ischemic myocardium, compared to normal myocardium. Therefore, with the localized induction of VEGF and the low cytotoxicity of WSLP, the pEpo-SV-VEGF/WSLP system may be helpful to eventually treat ischemic heart disease.