Acetylated α-Tubulin Regulated by N-Acetyl-Seryl-Aspartyl-Lysyl-Proline(Ac-SDKP) Exerts the Anti-fibrotic Effect in Rat Lung Fibrosis Induced by Silica.

Wang Xiaojun,Wang Ruimin,Wei Zhongqiu,Zhang Lijuan,Zhang Xianghong,Xu Hong,Darrell Brann,Liu Yan,Gao Xuemin,Li Shifeng,Yang Fang,Zhang Bonan,Xu Dingjie

doi:10.1038/srep32257

Abstract

Silicosis is the most serious occupational disease in China. The objective of this study was to screen various proteins related to mechanisms of the pathogenesis of silicosis underlying the anti-fibrotic effect of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) using proteomic profile analysis. We also aimed to explore a potential mechanism of acetylated α-tubulin (α-Ac-Tub) regulation by Ac-SDKP. Two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF/TOF MS) were used to assess the different protein expression profiles between control and silicosis rats treated with or without Ac-SDKP. Twenty-nine proteins were identified to be potentially involved in the progression of silicosis and the anti-fibrotic effect of Ac-SDKP. Our current study finds that 1) the lost expression of Ac-Tub-α may be a new mechanism in rat silicosis; 2) treatment of silicotic rats with N-acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) inhibits myofibroblast differentiation and collagen deposition accompanied by stabilizing the expression of α-Ac-Tub in vivo and in vitro, which is related with deacetylase family member 6 (HDAC6) and α-tubulin acetyl transferase (α-TAT1). Our data suggest that α-Ac-Tub regulation by Ac-SDKP may potentially be a new anti-fibrosis mechanism.

Highlights

The naturally occurring tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) was recognized as an anti-fibrotic peptide that contributes to the prevention of inflammation and fibrosis in cardiovascular[1], autoimmune[2], pulmonary[3], liver[4] and renal diseases[5]
We explored 1) the differential protein profile related to rats with silicosis that were treated with Ac-SDKP; 2) the expression dynamics of α-Ac-Tub in the rat silicosis model; and 3) the differential expression of α-Ac-Tub regulated by histone deacetylase family member 6 (HDAC6) and α-TAT1 in terms of the anti-silicosis effect of Ac-SDKP, the inhibition of myofibroblast differentiation induced by angiotensin II (Ang II)
Our group previously reported that Ac-SDKP has a beneficial effect upon silicosis, which involved the attenuation of TGF-β1 and Ang II signaling, pulmonary fibroblast proliferation, and collagen synthesis via c-Jun N-terminal kinase (JNK) signaling, as well as the regulation of myofibroblast differentiation by serum response factor (SRF)[8,9]

Summary

Introduction

The naturally occurring tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) was recognized as an anti-fibrotic peptide that contributes to the prevention of inflammation and fibrosis in cardiovascular[1], autoimmune[2], pulmonary[3], liver[4] and renal diseases[5]. Ac-SDKP has been shown to inhibit cell proliferation, myofibroblast differentiation, and collagen deposition, effects that are regulated by transforming growth factor beta (TGF-β) signaling and the rennin-angiotensin system (RAS), among other systems[1,2,3,4,5,6,7]. These observations suggest that Ac-SDKP has an anti-fibrotic effect and that fibrotic diseases are mediated, at least in part, by the down-regulation of Ac-SDKP. We explored 1) the differential protein profile related to rats with silicosis that were treated with Ac-SDKP; 2) the expression dynamics of α-Ac-Tub in the rat silicosis model; and 3) the differential expression of α-Ac-Tub regulated by HDAC6 and α-TAT1 in terms of the anti-silicosis effect of Ac-SDKP, the inhibition of myofibroblast differentiation induced by Ang II

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Conclusion