Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing

Katsunari Makino, Masatoshi Jinnin, Jun Aoi, Ikko Kajihara, Takamitsu Makino, Satoshi Fukushima, Keisuke Sakai, Kazuhiko Nakayama, Noriaki Emoto, Masashi Yanagisawa, Hironobu Ihn

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Abstract

Endothelin (ET)-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF)-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF)-α and connective tissue growth factor (CTGF) were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.

Original languageEnglish (US)
Article numbere97972
JournalPLoS One
Volume9
Issue number5
DOIs
StatePublished - May 22 2014

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endothelins
Endothelial cells
Endothelin-1
tissue repair
fibrosis
skin (animal)
Wound Healing
endothelial cells
Skin
Fibrosis
Endothelial Cells
Knockout Mice
mice
transforming growth factors
Transforming Growth Factors
Connective Tissue Growth Factor
Bleomycin
tumor necrosis factors
animal injuries
connective tissues

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Makino, K., Jinnin, M., Aoi, J., Kajihara, I., Makino, T., Fukushima, S., ... Ihn, H. (2014). Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing. PLoS One, 9(5), [e97972]. https://doi.org/10.1371/journal.pone.0097972

Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing. / Makino, Katsunari; Jinnin, Masatoshi; Aoi, Jun; Kajihara, Ikko; Makino, Takamitsu; Fukushima, Satoshi; Sakai, Keisuke; Nakayama, Kazuhiko; Emoto, Noriaki; Yanagisawa, Masashi; Ihn, Hironobu.

In: PLoS One, Vol. 9, No. 5, e97972, 22.05.2014.

Research output: Contribution to journalArticle

Makino, K, Jinnin, M, Aoi, J, Kajihara, I, Makino, T, Fukushima, S, Sakai, K, Nakayama, K, Emoto, N, Yanagisawa, M & Ihn, H 2014, 'Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing', PLoS One, vol. 9, no. 5, e97972. https://doi.org/10.1371/journal.pone.0097972
Makino, Katsunari ; Jinnin, Masatoshi ; Aoi, Jun ; Kajihara, Ikko ; Makino, Takamitsu ; Fukushima, Satoshi ; Sakai, Keisuke ; Nakayama, Kazuhiko ; Emoto, Noriaki ; Yanagisawa, Masashi ; Ihn, Hironobu. / Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing. In: PLoS One. 2014 ; Vol. 9, No. 5.
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AU - Fukushima, Satoshi

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