Somatic gene transfer continues to have potential for the study and therapy of cardiovascular disease. We have developed a modular, self-assembling, nonviral system consisting of Lipofectin, integrin-targeting peptides, and plasmid DNA (LID) and we have applied this to a model of vascular injury, rat carotid angioplasty. Marker gene studies identified transfection of adventitial cells after vector delivery to that layer. Human tissue inhibitor of metalloproteinase-1 (hTIMP-1) was tested as a therapeutic gene product after direct application to the exposed adventitial layer. Vascular LID.hTIMP-1 transfection was confirmed by polymerase chain reaction and gene expression by immunohistochemistry at 7 days. Neointimal areas were 0.160 +/- 0.078 and 0.225 +/- 0.052 mm(2) for LID.hTIMP-1-transfected (n = 14) and LID.pCI-transfected (n = 12) vessels, respectively, at 14 days, and 0.116 +/- 0.068 mm(2) (n = 14) and 0.194 +/- 0.095 mm(2) (n = 14), respectively, at 28 days, representing a 29 and 40% reduction in neointimal hyperplasia at 14 and 28 days, respectively, after balloon dilatation. Neointima-to-media ratios were similarly reduced. In addition, expansile remodeling after balloon injury was inhibited at 14 days, the area within the external elastic lamina being 0.50 +/- 0.02 and 0.61 +/- 0.02 mm(2) in LID.hTIMP-1- and LID.pCI-transfected arteries, respectively (p < 0.0005). We have demonstrated an effective system of therapeutic gene transfer, particularly targeting the arterial adventitia, where transfer of genes involved in matrix remodeling and cell migration may be useful.

译文

:体细胞基因转移对于心血管疾病的研究和治疗仍然具有潜力。我们已经开发了由脂转染蛋白,整合素靶向肽和质粒DNA(LID)组成的模块化,自组装非病毒系统,并将其应用于血管损伤,大鼠颈动脉血管成形术的模型。标记基因研究确定了载体递送至该层后外膜细胞的转染。直接应用于暴露的外膜层后,将人类组织金属蛋白酶-1(hTIMP-1)抑制剂作为治疗性基因产物进行了测试。在第7天通过聚合酶链反应和基因表达通过免疫组织化学证实了血管LID.hTIMP-1转染。 LID.hTIMP-1转染(n = 14)和LID.pCI转染(n = 12)的血管分别在14天和0.116处的新内膜面积分别为0.160 /-0.078和0.225 /-0.052 mm(2)。 /-在28天时分别为0.068 mm(2)(n = 14)和0.194 /-0.095 mm(2)(n = 14),分别表示在14天和28天时内膜增生减少了29%和40% ,球囊扩张后。新内膜与培养基的比例也降低了。此外,气囊损伤后的重塑在第14天被抑制,LID.hTIMP-1-和LID.pCI转染的动脉中,外部弹性层的面积分别为0.50 /-0.02和0.61 /-0.02 mm(2),分别为(p <0.0005)。我们已经证明了一种有效的治疗性基因转移系统,尤其是靶向动脉外膜,其中涉及基质重塑和细胞迁移的基因转移可能是有用的。

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