Yao En-Hui, Fukuda Noboru, Ueno Takahiro, Matsuda Hiroyuki, Nagase Hiroki, Matsumoto Yoshiaki, Sugiyama Hiroshi, Matsumoto Koichi
Division of Nephrology, Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
Cardiovasc Res. 2009 Mar 1;81(4):797-804. doi: 10.1093/cvr/cvn355. Epub 2008 Dec 20.
Although the use of drug-eluting stents (DESs) has been shown to limit neointima hyperplasia, currently available DESs may adversely affect re-endothelialization. To evaluate whether a novel gene silencer pyrrole-imidazole (PI) polyamide targeting transforming growth factor (TGF)-beta1 is a candidate agent for the DESs, we examined the effects of PI polyamide targeting the TGF-beta1 promoter on neointimal formation in rat carotid artery after balloon injury.
PI polyamide was designed to span the boundary of the AP-1 binding site of the TGF-beta1 promoter. After inducing balloon injury to arteries, incubation with PI polyamide was carried out for 10 min. Neointimal thickening and re-endothelialization were evaluated at 21 days after injury. Fluoresceinisothiocyanate-labelled PI polyamide was distributed into most of the nuclei in the injured artery without any delivery reagents. PI polyamide (100 microg) significantly inhibited neointimal thickening at 21 days after injury by 57%. PI polyamide targeting TGF-beta1 significantly decreased the expression of TGF-beta1 mRNA and protein in the artery at 3 days after injury and also suppressed the expression of connective tissue growth factor (CTGF), fibronectin, collagen type 1, and lectin-like ox-LDL receptor-1 mRNAs. A morphometric analysis showed that PI polyamide targeting TGF-beta1 accelerated re-endothelialization in the injured artery.
These findings suggest that the synthetic PI polyamide targeting the TGF-beta1 promoter may have the potential to suppress neointimal hyperplasia after arterial injury by the down-regulation of TGF-beta1 and CTGF and the reduction of the extracellular matrix. As a result, PI polyamide targeting TGF-beta1 may therefore be a potentially effective agent for the treatment of in-stent restenosis, as a candidate agent for the next-generation DES.
尽管药物洗脱支架（DESs）的使用已被证明可限制新生内膜增生，但目前可用的DESs可能会对再内皮化产生不利影响。为了评估一种靶向转化生长因子（TGF）-β1的新型基因沉默剂吡咯-咪唑（PI）聚酰胺是否是DESs的候选药物，我们研究了靶向TGF-β1启动子的PI聚酰胺对大鼠颈动脉球囊损伤后新生内膜形成的影响。
PI聚酰胺被设计为跨越TGF-β1启动子的AP-1结合位点边界。在对动脉进行球囊损伤后，与PI聚酰胺孵育10分钟。在损伤后21天评估新生内膜增厚和再内皮化情况。异硫氰酸荧光素标记的PI聚酰胺在没有任何递送试剂的情况下分布到损伤动脉的大多数细胞核中。PI聚酰胺（100微克）在损伤后21天显著抑制新生内膜增厚达57%。靶向TGF-β1的PI聚酰胺在损伤后3天显著降低动脉中TGF-β1 mRNA和蛋白的表达，还抑制结缔组织生长因子（CTGF）、纤连蛋白、I型胶原和凝集素样氧化型低密度脂蛋白受体-1 mRNA的表达。形态计量分析表明，靶向TGF-β1的PI聚酰胺加速了损伤动脉的再内皮化。
这些发现表明，靶向TGF-β1启动子的合成PI聚酰胺可能具有通过下调TGF-β1和CTGF以及减少细胞外基质来抑制动脉损伤后新生内膜增生的潜力。因此，靶向TGF-β1的PI聚酰胺作为下一代DES的候选药物，可能是治疗支架内再狭窄的潜在有效药物。
