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转化生长因子-β1/成纤维细胞生长因子-2信号传导介导15-羟基二十碳四烯酸诱导的外膜成纤维细胞向肌成纤维细胞的分化。

TGF-β1/FGF-2 signaling mediates the 15-HETE-induced differentiation of adventitial fibroblasts into myofibroblasts.

作者信息

Zhang Li, Chen Yan, Li Guixia, Chen Minggang, Huang Wei, Liu Yanrui, Li Yumei

机构信息

Department of Pharmacology, Harbin Medical University-Daqing, Xinyang Road 39, Daqing, Heilongjiang Province, 163319, China.

Daqing Qil Fields General Hospital, Heilongjiang, Daqing, Heilongjiang Province, 163319, China.

出版信息

Lipids Health Dis. 2016 Jan 5;15:2. doi: 10.1186/s12944-015-0174-3.

DOI:10.1186/s12944-015-0174-3
PMID:26729053
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4700586/
Abstract

BACKGROUND

Pulmonary adventitial fibroblasts (PAFs) are activated under stress stimuli leading to their differentiation into myofibroblasts, which is involved in vessel remodeling. 15-HETE is known as an important factor in vessel remodeling under hypoxia; however, the role of 15-HETE in PAF phenotypic alteration is not clear.

RESULTS

The effect of 15-HETE on PAF phenotypic alterations was investigated in the present study. PAFs were treated with 15-HETE (0.5 μM) for 24 h, and the myofibroblast marker α-smooth muscle actin (α-SMA) was analyzed. The 15-HETE induced α-SMA expression and cell morphology. 15-HETE upregulated FGF-2 levels in PAFs, and knockdown FGF-2 by siRNAs blocked the enhanced α-SMA expression induced by 15-HETE. p38 kinase was activated, and blocked depressed 15-HETE-induced FGF-2 expression. The downstream of p38 pathway, Egr-1 activation, was also raised by 15-HETE treatment, and silenced Egr-1 suppressed the 15-HETE-induced upregulation of FGF-2. TGF-β1 was upregulated with FGF-2 treatment, and α-SMA expression induced by FGF-2 was inhibited after the cell was transferred with TGF-β1 siRNA. Meanwhile, FGF-2 increased α-SMA expression and improved proliferation, which was associated with p27(kip1) and cyclin E variation.

CONCLUSIONS

The above results suggest that p38/Egr-1 pathway-mediated FGF-2 is involved in 15-HETE-induced differentiation of PAFs into myofibroblasts and cell proliferation.

摘要

背景

肺外膜成纤维细胞（PAFs）在应激刺激下被激活，导致其分化为肌成纤维细胞，这与血管重塑有关。15-羟基二十碳四烯酸（15-HETE）是低氧条件下血管重塑的一个重要因素；然而，15-HETE在PAF表型改变中的作用尚不清楚。

结果

本研究探讨了15-HETE对PAF表型改变的影响。用15-HETE（0.5μM）处理PAFs 24小时，分析肌成纤维细胞标志物α-平滑肌肌动蛋白（α-SMA）。15-HETE诱导α-SMA表达和细胞形态改变。15-HETE上调PAFs中碱性成纤维细胞生长因子-2（FGF-2）水平，通过小干扰RNA（siRNAs）敲低FGF-2可阻断15-HETE诱导的α-SMA表达增强。p38激酶被激活，阻断其活性可抑制15-HETE诱导的FGF-2表达。15-HETE处理还可增强p38信号通路下游早期生长反应因子-1（Egr-1）的激活，沉默Egr-1可抑制15-HETE诱导的FGF-2上调。用FGF-2处理可上调转化生长因子-β1（TGF-β1），用TGF-β1 siRNA转染细胞后可抑制FGF-2诱导的α-SMA表达。同时，FGF-2增加α-SMA表达并促进细胞增殖，这与p27（kip1）和细胞周期蛋白E的变化有关。

结论

上述结果表明，p38/Egr-1信号通路介导的FGF-2参与了15-HETE诱导的PAFs向肌成纤维细胞的分化及细胞增殖。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/cba1ce63040f/12944_2015_174_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/944640661f2a/12944_2015_174_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/0752327dd36a/12944_2015_174_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/fa15b0715251/12944_2015_174_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/85550be10648/12944_2015_174_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/cba1ce63040f/12944_2015_174_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/944640661f2a/12944_2015_174_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/0752327dd36a/12944_2015_174_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/fa15b0715251/12944_2015_174_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/85550be10648/12944_2015_174_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b688/4700586/cba1ce63040f/12944_2015_174_Fig5_HTML.jpg

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