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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 20, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn355
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

A Pyrrole-Imidazole Polyamide Targeting TGF-β1 Inhibits Restenosis and Preserves Endothelialization in the Injured Artery

En-Hui Yao1, Noboru Fukuda1,2, Takahiro Ueno1, Hiroyuki Matsuda2, Hiroki Nagase2,3, Yoshiaki Matsumoto4, Hiroshi Sugiyama5 and Koichi Matsumoto1

1 Division of Nephrology Hypertension and Endocrinology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
2 Advanced Research Institute of the Sciences and Humanities, Nihon University, Tokyo Japan
3 Division of Cancer Genetics, Department of Advanced Medical Science, Nihon University School of Medicine, Tokyo, Japan
4 Department of Clinical Pharmacokinetics, College of Pharmacy, Nihon University, Chiba, Japan
5 Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto, Japan

Address correspondence to: Dr. Noboru Fukuda, Advanced Research Institute of the Sciences and Humanities, Nihon University, Ooyaguchi-kami 30-1, Itabashi-ku, Tokyo 173-8610, Japan. Phone: 81-3-3972-8111; Fax: 81-3-3972-8666; E-mail: fukudan{at}med.nihon-u.ac.jp

Aims: Although the use of drug-eluting stents (DESs) has been shown to limit neointima hyperplasia, currently available DESs may adversely affect reendothelialization. To evaluate whether a novel gene silencer pyrrole-imidazole (PI) polyamide targeting transforming growth factor (TGF)-β1 is a candidate agent for the DESs, we examined the effects of PI polyamide targeting the TGF-β1 promoter on neointimal formation in rat carotid artery after balloon injury.

Methods: PI polyamide was designed to span the boundary of the AP-1 binding site of the TGF-β1 promoter. After inducing balloon injury to arteries, incubation with PI polyamide was carried out for 10min. Neointimal thickening and reendothelialization were evaluated at 21 days after injury.

Results: FITC-labeled PI polyamide was distributed into most of the nuclei in the injured artery without any delivery reagents. PI polyamide (100µg) significantly inhibited the neointimal thickening at 21 days after injury by 57%. PI polyamide targeting TGF-β1 significantly decreased the expression of TGF-β1 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-β1 accelerated reendothelialization in the injured artery.

Conclusion: These findings suggest that the synthetic PI polyamide targeting the TGF-β1 promoter may have the potential to suppress neointimal hyperplasia after arterial injury by the down-regulation of TGF-β1 and CTGF and the reduction of the extracellular matrix. As a result, PI polyamide targeting TGF-β1 may therefore be a potentially effective agent for the treatment of in-stent restenosis, as a candidate agent for the next-generation DES.

KEYWORDS pyrrole-imidazole polyamide; transforming growth factor-β1; rat; restenosis

Time for primary review: 60 Days


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