TY - JOUR
T1 - Transcriptional inhibition of hypertrophic scars by a gene silencer, pyrrole-imidazole polyamide, targeting the TGF-Β1 promoter
AU - Washio, Hisayo
AU - Fukuda, Noboru
AU - Matsuda, Hiroyuki
AU - Nagase, Hiroki
AU - Watanabe, Takayoshi
AU - Matsumoto, Yoshiaki
AU - Terui, Tadashi
PY - 2011/10
Y1 - 2011/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80052822707&partnerID=8YFLogxK
U2 - 10.1038/jid.2011.150
DO - 10.1038/jid.2011.150
M3 - Article
AN - SCOPUS:80052822707
SN - 0022-202X
VL - 131
SP - 1987
EP - 1995
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 10
ER -