Journal
CARDIOVASCULAR RESEARCH
Volume 81, Issue 4, Pages 797-804Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvn355
Keywords
Pyrrole-imidazole polyamide; Transforming growth factor-beta 1; Rat; Restenosis
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Funding
- Japanese Ministry of Education, Science, Sports
- Nihon University Multidisciplinary Research Grant for 2006
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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)-beta 1 is a candidate agent for the DESs, we examined the effects of PI polyamide targeting the TGF-beta 1 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-beta 1 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 mu g) significantly inhibited neointimal thickening at 21 days after injury by 57%. PI polyamide targeting TGF-beta 1 significantly decreased the expression of TGF-beta 1 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-beta 1 accelerated re-endothelialization in the injured artery. These findings suggest that the synthetic PI polyamide targeting the TGF-beta 1 promoter may have the potential to suppress neointimal hyperplasia after arterial injury by the down-regulation of TGF-beta 1 and CTGF and the reduction of the extracellular matrix. As a result, PI polyamide targeting TGF-beta 1 may therefore be a potentially effective agent for the treatment of in-stent restenosis, as a candidate agent for the next-generation DES.
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