Influence of the interaction between Ac-SDKP and ang II on the pathogenesis and development of silicotic fibrosis

Yi Zhang, Fang Yang, Yan Liu, Hai Bing Peng, Yu Cong Geng, Shi Feng Li, Hong Xu, Li Yan Zhu, Xiu Hong Yang, Darrell W Brann

Research output: Contribution to journalArticle

Abstract

N-acetyl-seryl-aspartyl-lysyl-proline(Ac-SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin-angiotensin system, angiotensin-converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac-SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac-SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac-SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac-SDKP decreased. Ac-SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac-SDKP treatment had an anti-fibrotic effect in vivo. Compared with the silicosis group, the expression of α-smooth muscle actin (α-SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase-1 (MMP-1) expression and the MMP-1/tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio was increased in the Ac-SDKP treatment group. In vitro, pre-treatment with Ac-SDKP or valsartan attenuated the expression of a-SMA, Col I, Fn and AT1 in Ang II-induced fibroblasts. In addition, MMP-1 expression and the MMP-1/TIMP-1 ratio were significantly higher in Ac-SDKP and valsartan pre-treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac-SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac-SDKP protects against silicotic fibrosis by inhibiting Ang II-induced myofibroblast differentiation and extracellular matrix production.

Original languageEnglish (US)
Pages (from-to)7467-7476
Number of pages10
JournalMolecular Medicine Reports
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Angiotensin II
Fibrosis
Valsartan
Peptidyl-Dipeptidase A
Silicosis
Matrix Metalloproteinase 1
Tissue Inhibitor of Metalloproteinase-1
Myofibroblasts
Fibroblasts
Fibronectins
goralatide
Collagen
Exposure controls
Thymosin
Lung
Oligopeptides
Angiotensin Type 1 Receptor
Angiotensins
Renin-Angiotensin System
Renin

Keywords

  • Myofibroblast
  • N-acetyl-seryl-aspartyl-lysyl-proline
  • Reninangiotensin system
  • Silicosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Influence of the interaction between Ac-SDKP and ang II on the pathogenesis and development of silicotic fibrosis. / Zhang, Yi; Yang, Fang; Liu, Yan; Peng, Hai Bing; Geng, Yu Cong; Li, Shi Feng; Xu, Hong; Zhu, Li Yan; Yang, Xiu Hong; Brann, Darrell W.

In: Molecular Medicine Reports, Vol. 17, No. 6, 01.06.2018, p. 7467-7476.

Research output: Contribution to journalArticle

Zhang, Yi ; Yang, Fang ; Liu, Yan ; Peng, Hai Bing ; Geng, Yu Cong ; Li, Shi Feng ; Xu, Hong ; Zhu, Li Yan ; Yang, Xiu Hong ; Brann, Darrell W. / Influence of the interaction between Ac-SDKP and ang II on the pathogenesis and development of silicotic fibrosis. In: Molecular Medicine Reports. 2018 ; Vol. 17, No. 6. pp. 7467-7476.
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AU - Peng, Hai Bing

AU - Geng, Yu Cong

AU - Li, Shi Feng

AU - Xu, Hong

AU - Zhu, Li Yan

AU - Yang, Xiu Hong

AU - Brann, Darrell W

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N2 - N-acetyl-seryl-aspartyl-lysyl-proline(Ac-SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin-angiotensin system, angiotensin-converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac-SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac-SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac-SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac-SDKP decreased. Ac-SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac-SDKP treatment had an anti-fibrotic effect in vivo. Compared with the silicosis group, the expression of α-smooth muscle actin (α-SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase-1 (MMP-1) expression and the MMP-1/tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio was increased in the Ac-SDKP treatment group. In vitro, pre-treatment with Ac-SDKP or valsartan attenuated the expression of a-SMA, Col I, Fn and AT1 in Ang II-induced fibroblasts. In addition, MMP-1 expression and the MMP-1/TIMP-1 ratio were significantly higher in Ac-SDKP and valsartan pre-treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac-SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac-SDKP protects against silicotic fibrosis by inhibiting Ang II-induced myofibroblast differentiation and extracellular matrix production.

AB - N-acetyl-seryl-aspartyl-lysyl-proline(Ac-SDKP) is a natural tetrapeptide that is released from thymosin β4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin-angiotensin system, angiotensin-converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac-SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac-SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac-SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac-SDKP decreased. Ac-SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac-SDKP treatment had an anti-fibrotic effect in vivo. Compared with the silicosis group, the expression of α-smooth muscle actin (α-SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase-1 (MMP-1) expression and the MMP-1/tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio was increased in the Ac-SDKP treatment group. In vitro, pre-treatment with Ac-SDKP or valsartan attenuated the expression of a-SMA, Col I, Fn and AT1 in Ang II-induced fibroblasts. In addition, MMP-1 expression and the MMP-1/TIMP-1 ratio were significantly higher in Ac-SDKP and valsartan pre-treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac-SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac-SDKP protects against silicotic fibrosis by inhibiting Ang II-induced myofibroblast differentiation and extracellular matrix production.

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