Cargando…

Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation

Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that gi...

Descripción completa

Detalles Bibliográficos
Autores principales: Yu, Lan, Bian, Xiyun, Zhang, Chunyan, Wu, Zhouying, Huang, Na, Yang, Jie, Jin, Wen, Feng, Zongqi, Li, Dongfang, Huo, Xue, Wu, Ting, Jiang, Zhongmin, Liu, Xiaozhi, Sun, Dejun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9192210/
https://www.ncbi.nlm.nih.gov/pubmed/35707278
http://dx.doi.org/10.1155/2022/8002566
_version_ 1784726185487368192
author Yu, Lan
Bian, Xiyun
Zhang, Chunyan
Wu, Zhouying
Huang, Na
Yang, Jie
Jin, Wen
Feng, Zongqi
Li, Dongfang
Huo, Xue
Wu, Ting
Jiang, Zhongmin
Liu, Xiaozhi
Sun, Dejun
author_facet Yu, Lan
Bian, Xiyun
Zhang, Chunyan
Wu, Zhouying
Huang, Na
Yang, Jie
Jin, Wen
Feng, Zongqi
Li, Dongfang
Huo, Xue
Wu, Ting
Jiang, Zhongmin
Liu, Xiaozhi
Sun, Dejun
author_sort Yu, Lan
collection PubMed
description Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-β1, but GA could reverse the effects of TGF-β1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-β1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-β1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-β1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.
format Online
Article
Text
id pubmed-9192210
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-91922102022-06-14 Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation Yu, Lan Bian, Xiyun Zhang, Chunyan Wu, Zhouying Huang, Na Yang, Jie Jin, Wen Feng, Zongqi Li, Dongfang Huo, Xue Wu, Ting Jiang, Zhongmin Liu, Xiaozhi Sun, Dejun Oxid Med Cell Longev Research Article Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-β1, but GA could reverse the effects of TGF-β1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-β1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-β1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-β1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF. Hindawi 2022-06-06 /pmc/articles/PMC9192210/ /pubmed/35707278 http://dx.doi.org/10.1155/2022/8002566 Text en Copyright © 2022 Lan Yu et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Yu, Lan
Bian, Xiyun
Zhang, Chunyan
Wu, Zhouying
Huang, Na
Yang, Jie
Jin, Wen
Feng, Zongqi
Li, Dongfang
Huo, Xue
Wu, Ting
Jiang, Zhongmin
Liu, Xiaozhi
Sun, Dejun
Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation
title Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation
title_full Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation
title_fullStr Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation
title_full_unstemmed Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation
title_short Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation
title_sort ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting smad4 sumoylation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9192210/
https://www.ncbi.nlm.nih.gov/pubmed/35707278
http://dx.doi.org/10.1155/2022/8002566
work_keys_str_mv AT yulan ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT bianxiyun ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT zhangchunyan ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT wuzhouying ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT huangna ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT yangjie ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT jinwen ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT fengzongqi ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT lidongfang ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT huoxue ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT wuting ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT jiangzhongmin ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT liuxiaozhi ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation
AT sundejun ginkgolicacidimprovesbleomycininducedpulmonaryfibrosisbyinhibitingsmad4sumoylation