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J Dermatol Sci. 2019 Apr;94(1):205-212. doi: 10.1016/j.jdermsci.2019.02.003. Epub 2019 Mar 12.

COA-Cl prevented TGF-β1-induced CTGF expression by Akt dephosphorylation in normal human dermal fibroblasts, and it attenuated skin fibrosis in mice models of systemic sclerosis.

Author information

1
Department of Dermatology, Kagawa University, Kagawa, Japan. Electronic address: kozo@kms.ac.jp.
2
School of Medicine, Kagawa University, Kagawa, Japan.
3
Department of Clinical Engineering, Morinomiya University of Medical Sciences, Osaka, Japan.
4
Department of Pharmaco-Bio-Informatics, Kagawa University, Kagawa, Japan.
5
Department of Cardiovascular Physiology, Kagawa University, Kagawa, Japan.
6
Department of Dermatology, Kagawa University, Kagawa, Japan.

Abstract

BACKGROUND:

Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. Although transforming growth factor (TGF)-β1-induced connective tissue growth factor (CTGF/CCN2) expression has been presented in SSc fibrosis, the therapeutic potential of targeting CTGF in SSc has not been fully explored. COA-Cl is a novel nucleic acid analog, which is reported to have pleiotropic beneficial biologic effects.

OBJECTIVE:

We examine the effects of COA-Cl on TGF-β1-induced CTGF expression in normal human dermal fibroblast (NHDF). We also examined the effects of COA-Cl on CTGF expression in a mouse SSc model of angiotensin II (Ang II)-induced skin fibrosis.

METHODS:

NHDF was cultured for in vitro experiments. For in vivo experiments, C57BL/6J mice were treated with Ang II for 14 days by subcutaneous osmotic pump. Quantitative real-time polymerase chain reaction, western blot analysis, immunohistochemical staining and immunofluorescence staining were performed to examine the expression levels of CTGF and phosphorylation levels of Smad2/3, ERK1/2 and Akt.

RESULTS:

COA-Cl attenuated the TGF-β1-induced expression of both CTGF mRNA and protein in NHDF. Although COA-Cl did not alter the TGF-β1-induced phosphorylation of Smad2/3 or ERK1/2, it reduced the TGF-β1-induced phosphorylation levels of Akt in NHDF. Notably, COA-Cl dephosphorylated the Akt of lysates of TGF-β1-treated NHDF. COA-Cl reduced the levels of CTGF mRNA, CTGF protein, dermal thickness, collagen content and Akt phosphorylation in the skin of mice SSc model.

CONCLUSION:

These results imply that the inhibition of TGF-β1-induced CTGF expression by COA-Cl may be a therapeutic approach for SSc.

KEYWORDS:

Akt; Angiotensin II; COA-Cl; CTGF; TGF-β1

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