Lee M, Rentz J, Bikram M, Han S, Bull D A, Kim S W
Clinical Research Center, College of Medicine, Inha University, Incnan, Korea.
Gene Ther. 2003 Sep;10(18):1535-42. doi: 10.1038/sj.gt.3302034.
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 myo-cardium. 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.
采用编码血管内皮生长因子（VEGF）的基因进行治疗性血管生成是心血管疾病一种新的潜在治疗方法。然而，不受调控的VEGF介导的血管生成有可能促进肿瘤生长、加速糖尿病增殖性视网膜病变并促使动脉粥样硬化斑块破裂。为了安全有效，VEGF基因治疗必须受到调控。为了限制病理性血管生成的风险，我们利用促红细胞生成素（Epo）增强子和水溶性脂聚合物（WSLP）开发了一种缺氧诱导型VEGF基因治疗系统。通过将Epo增强子插入猿猴病毒40（SV40）启动子上游或pSV-VEGF的聚腺苷酸（A）信号下游构建了pEpo-SV-VEGF或pSV-VEGF-Epo。体外转染表明，pEpo-SV-VEGF而非pSV-VEGF-Epo可在缺氧细胞中诱导VEGF表达。此外，由Epo-SV-VEGF转染并经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复合物表明，与正常心肌相比，缺血心肌中可诱导VEGF表达。因此，鉴于VEGF的局部诱导以及WSLP的低细胞毒性，pEpo-SV-VEGF/WSLP系统可能最终有助于治疗缺血性心脏病。
