A pyrrole-imidazole polyamide targeting transforming growth factor-beta1 inhibits restenosis and preserves endothelialization in the injured artery.

Abstract

AIMS:

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.

METHODS AND RESULTS:

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.

CONCLUSION:

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.

• Authors: En-Hui Yao, Noboru Fukuda, Takahiro Ueno, Hiroyuki Matsuda, Hiroki Nagase, Yoshiaki Matsumoto, Hiroshi Sugiyama, Koichi Matsumoto
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 81 Issue 4 Pg. 797-804 (Mar 01 2009) ISSN: 1755-3245 [Electronic] England
• PMID: 19098300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCN2 protein, rat
• Collagen Type I
• Fibronectins
• Imidazoles
• Nylons
• OLR1 protein, rat
• Pyrroles
• RNA, Messenger
• Scavenger Receptors, Class E
• Transforming Growth Factor beta1
• Connective Tissue Growth Factor

Topics

• Animals
• Carotid Artery Injuries (drug therapy, metabolism, pathology)
• Carotid Stenosis (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Collagen Type I (metabolism)
• Connective Tissue Growth Factor (metabolism)
• Disease Models, Animal
• Endothelium, Vascular (drug effects, metabolism, pathology)
• Fibronectins (metabolism)
• Gene Silencing
• Hyperplasia
• Imidazoles (metabolism, pharmacology)
• Male
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Nylons (metabolism, pharmacology)
• Promoter Regions, Genetic (drug effects)
• Pyrroles (metabolism, pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Inbred WKY
• Scavenger Receptors, Class E (metabolism)
• Secondary Prevention
• Transforming Growth Factor beta1 (genetics, metabolism)