Ohtani K, Egashira K, Usui M, Ishibashi M, Hiasa K-I, Zhao Q, Aoki M, Kaneda Y, Morishita R, Takeshita A
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Gene Ther. 2004 Jan;11(2):126-32. doi: 10.1038/sj.gt.3302153.
Early growth response factor-1 (Egr-1) is a transcription factor that is rapidly activated after vascular injury and thus might contribute to vascular proliferation and inflammation. We hypothesized that Egr-1 might therefore be a therapeutic target against restenosis. Hypercholesterolemic rabbits were intraluminally administered synthetic DNA as a 'decoy' against Egr-1 immediately after carotid artery balloon injury. Efficient transfection was confirmed by the delivery of a fluorescence-labeled decoy. Gel mobility-shift assay showed increased Egr-1 activity after balloon injury and its prevention by Egr-1 decoy transfection in vivo. Egr-1 decoy transfection attenuated early inflammation and proliferation and later neointimal hyperplasia. In addition, Egr-1 decoy transfection reduced gene expression and protein production of Egr-1-dependent genes such as platelet-derived growth factor-B, transforming growth factor-beta1, and monocyte chemoattractant protein-1. The Egr-1 pathway has an essential role in the pathogenesis of neointimal hyperplasia after balloon injury in hypercholesterolemic rabbits. This decoy strategy is a potential practical form of therapy for human restenosis.
早期生长反应因子-1（Egr-1）是一种转录因子，在血管损伤后会迅速被激活，因此可能与血管增殖和炎症有关。我们推测，Egr-1可能是预防再狭窄的治疗靶点。对高胆固醇血症兔进行颈动脉球囊损伤后，立即向管腔内注入合成DNA作为针对Egr-1的“诱饵”。通过荧光标记诱饵的递送证实了有效转染。凝胶迁移率变动分析显示，球囊损伤后Egr-1活性增加，而体内Egr-1诱饵转染可预防这种增加。Egr-1诱饵转染减轻了早期炎症和增殖以及后期的内膜增生。此外，Egr-1诱饵转染降低了Egr-1依赖性基因（如血小板衍生生长因子-B、转化生长因子-β1和单核细胞趋化蛋白-1）的基因表达和蛋白质产生。Egr-1通路在高胆固醇血症兔球囊损伤后内膜增生的发病机制中起重要作用。这种诱饵策略是治疗人类再狭窄的一种潜在实用疗法。
