title: Transcriptional inhibition of hypertrophic scars by a gene silencer, pyrrole-imidazole polyamide, targeting the TGF-β1 promoter.
abstract: Synthetic pyrrole-imidazole (PI) polyamides bind to the minor groove of double-helical DNA with high affinity and specificity, and inhibit the transcription of corresponding genes. We examined the effects of a transforming growth factor (TGF)-β1-targeted PI polyamide (Polyamide) on hypertrophic skin scars in rats. Hypertrophic scars were created dorsally in rats by incisions. FITC-labeled Polyamide was injected to investigate its distribution in the skin. Expression of TGF-β1, connective tissue growth factor (CTGF), collagen type1, and fibronectin mRNAs was evaluated by reverse transcription PCR analysis. The extent of fibrosis and the expression of TGF-β1 were evaluated histologically and immunohistochemically. Polyamide was distributed in almost all nuclei of skin cells. Expression of TGF-β1 mRNA reached a peak at 3 days after skin incision. Expression of CTGF and extracellular matrix mRNAs was increased continuously even after the peak induction of TGF-β1 mRNA. Injection of Polyamide completely inhibited both the development of scars and the induction of growth factors and extracellular matrix mRNAs. The treatment also markedly inhibited fibrotic changes and reduced the numbers of vimentin-positive spindle-shaped fibroblasts. Injection of Polyamide also reduced established hypertrophic scars in rats. Thus, TGF-β1-targeted PI polyamide should be a feasible gene silencer for hypertrophic scars and keloids.
authors.affiliation: Division of Cutaneous Science, Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
authors.forename: Hisayo
authors.initials: H
authors.lastname: Washio
authors.forename: Noboru
authors.initials: N
authors.lastname: Fukuda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Matsuda
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nagase
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Terui
mesh_terms: D000818:Animals; D017439:Cicatrix, Hypertrophic / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D004247:DNA / Q000235:genetics; D005353:Fibronectins / Q000378:metabolism; D020868:Gene Silencing; D007093:Imidazoles / Q000494:pharmacology; D007627:Keloid / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008297:Male; D009757:Nylons / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000473:pathology; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D004247:DNA