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

体细胞基因转移继续具有研究和治疗心血管疾病的潜力。我们已经开发了一种模块化,自组装的非病毒系统,该系统由Lipofectin,整联蛋白靶向肽和质粒DNA (LID) 组成,并将其应用于血管损伤模型大鼠颈动脉血管成形术。标记基因研究确定了载体递送到该层后外膜细胞的转染。在直接施用于暴露的外膜层后,测试了metalloproteinase-1的人组织抑制剂 (hTIMP-1) 作为治疗性基因产物。血管盖。在第7天,通过聚合酶链反应和免疫组织化学证实hTIMP-1转染。在第14天,LID.hTIMP-1-transfected (n = 14) 和LID.pCI转染 (n = 12) 血管的内膜面积分别为0.160 +/- 0.078和0.225 +/-0.052毫米 (2),和0.116 +/-0.068毫米 (2) (n = 14) 和0.194 +/-0.095毫米 (2) (n = 14) 分别在第28天,分别表示在第14天和第28天新生内膜增生减少29和40%,球囊扩张后。新内膜与中膜比率也同样降低。此外,在第14天,球囊损伤后的扩张重塑受到抑制,LID.hTIMP-1和LID.pCI转染的动脉中,外部弹性层内的面积分别为0.50 +/- 0.02和0.61 +/-0.02毫米 (2) (p <0.0005)。我们已经证明了一种有效的治疗性基因转移系统,尤其是针对动脉外膜,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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