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Neuregulin induces CTGF expression in hypertrophic scarring fibroblasts

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Abstract

Hypertrophic scarring (HTS) is a common fibroproliferative disorder that typically follows thermal and other injuries involving the deep dermis. These pathogenic mechanisms are regulated by connective tissue growth factor (CTGF) and transforming growth factor-β. We found that neuregulin-1 (NRG1), as well as NRG receptors, HER-2, and HER-3 were upregulated in HTS fibroblasts (HTSF), compared with normal fibroblasts. Furthermore, NRG1 stimulation increased the expression of CTGF in HTSF. In the presence of inhibitors of PI3K, Src, Smad, or reactive oxygen species, the effect of NRG1 on CTGF expression decreased significantly. In particular, the combination of LY294002 or PP2 with SB431542 blocked NRG1-mediated CTGF expression in HTSF. Finally, we demonstrated that siRNA for CTGF, AG825, LY294002, and PP2, either alone or in co-treatment, effectively reduced extracellular matrix expression. Taken together, our results suggest that NRG1 is involved in fibrotic scar pathogenesis via PI3K- or Src-mediated CTGF expression.

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Abbreviations

HTS:

Hypertrophic scarring

CTGF:

Connective tissue growth factor

TGF-β:

Transforming growth factor-β

NRG:

Neuregulin

α-SMA:

α-Smooth muscle actin

ROS:

Reactive oxygen species

ECM:

Extracellular matrix

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

COL-I:

Collagen type I

Nox:

NADPH-oxidase

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Acknowledgments

We acknowledge Ji-Yeon Seo for comments and criticisms. These studies were supported by the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A084589) and the National Research Foundation of Korea (NRF-2010-013-E00019).

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Correspondence to Cheong Hoon Seo.

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Kim, JS., Choi, IG., Lee, BC. et al. Neuregulin induces CTGF expression in hypertrophic scarring fibroblasts. Mol Cell Biochem 365, 181–189 (2012). https://doi.org/10.1007/s11010-012-1258-2

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