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Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts

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Abstract

Cellular abelson (c-Abl), a non-receptor tyrosine kinase, is an important molecule in the pathogenesis of systemic sclerosis. There have been reports of beneficial effects of pharmacological tyrosine kinase inhibitors, such as imatinib mesylate, on fibrosis. However, these inhibitors affect multiple tyrosine kinases including c-Abl, c-kit, and platelet-derived growth factor receptor. The effects of selective inhibition of c-Abl using small interfering RNA (siRNA) on dermal fibrosis have not yet been explored. The aim of this study is to evaluate whether specific inhibition of c-Abl by siRNA can influence the transforming growth factor-β1 (TGF-β1)-induced fibrotic responses. Dermal fibroblasts from systemic sclerosis patients and healthy controls were transfected with c-Abl siRNA. The expression levels of collagen type I, fibronectin, connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) were measured at both the mRNA and protein levels in the absence or presence of TGF-β1 pro-fibrotic cytokine. In healthy dermal fibroblasts, the expression of collagen type 1, fibronectin, α-SMA, and CTGF mRNAs and proteins that were upregulated after stimulation with TGF-β1 was markedly decreased by c-Abl siRNA. Silencing of c-Abl via siRNA efficiently reduced the basal synthesis of collagen type I, fibronectin, α-SMA, and CTGF mRNAs and proteins in systemic sclerosis fibroblasts, but it had no effect on the baseline expression of these genes and proteins in healthy dermal fibroblasts. In conclusion, specific c-Abl gene silencing using siRNA effectively reduced fibrosis-related gene expression. Inhibition of c-Abl by siRNA may be a potential therapeutic approach for fibrotic diseases such as systemic sclerosis.

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Acknowledgments

This survey was supported by Iran National Science Foundation (INSF) (Grant No. 90001195) and Tehran university of Medical Sciences (Grant No. 90-03-41-13988). The authors would like to thank Dr. Ashjaee B for her kind help.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cell and Molecular Biology, School of biology, College of Science, University of Tehran, P.O. Box 141556455, Tehran, Iran

    Elham Karimizadeh, Nasrin Motamed & Saeideh Jafarinejad-Farsangi

  2. Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Kargar Ave, P.O. BOX 1411713137, Tehran, Iran

    Mahdi Mahmoudi, Ahmadreza Jamshidi, Habibeh Faridani & Farhad Gharibdoost

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  1. Elham Karimizadeh
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Correspondence to Nasrin Motamed or Farhad Gharibdoost.

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Karimizadeh, E., Motamed, N., Mahmoudi, M. et al. Attenuation of fibrosis with selective inhibition of c-Abl by siRNA in systemic sclerosis dermal fibroblasts. Arch Dermatol Res 307, 135–142 (2015). https://doi.org/10.1007/s00403-014-1532-0

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  • DOI: https://doi.org/10.1007/s00403-014-1532-0

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