MiR-21-Mediated Suppression of Smad7 Induces TGFβ1 and Can Be Inhibited by Activation of Nrf2 in Alcohol-Treated Lung Fibroblasts.
MiR-21-Mediated Suppression of Smad7 Induces TGFβ1 and Can Be Inhibited by Activation of Nrf2 in Alcohol-Treated Lung Fibroblasts.
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DOI：
10.1111/acer.13496
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Sueblinvong V
中科院分区：
文献类型：
--
作者：
Marts LT;Green DE;Mills ST;Murphy T;Sueblinvong V
我们先前证明，在急性肺损伤的小鼠模型中，慢性酒精摄入增加了肺成纤维细胞转化生长因子β1的表达，并增加了纤维增殖性丧失修复的风险。萝卜硫素可激活核因子(红系)样因子2(NRF2)，减轻酒精对转化生长因子β1的影响。然而，酒精增强或减弱转化生长因子β1在成纤维细胞中表达的机制尚不清楚。已有研究表明，microRNA(MiR)-21可抑制转化生长因子β-1信号抑制因子Smad7。在本研究中，我们假设酒精通过上调β-21的表达来增强转化生长因子Smad1的表达，从而抑制Smad7。原代培养小鼠肺成纤维细胞，检测miR-21基因表达、NRF2、NRF2调节的抗氧化酶、Smad7、STAT3和转化生长因子β1的基因和/或蛋白表达。检测α-SMA、Smad7和转化生长因子β-1蛋白的表达。同时，将NRF2沉默RNA(SiRNA)导入NIH3T3肺成纤维细胞，并培养±乙醇±SFP。检测miR-21、NRF2、Smad7和转化生长因子β-1的基因表达。酒精作用48小时后，成纤维细胞中MIR-21基因表达增加12倍，∼使Smad7基因和蛋白表达降低30%。同时，抑制miR-21可减弱酒精诱导的Smad7表达减少和转化生长因子β-1和α-平滑肌肌动蛋白表达的增加。SFP处理减轻了酒精对miR-21、Smad7、总和磷酸化的STAT3的影响，并恢复了Nrf2调节的抗氧化基因的表达。沉默NRF2可阻止SFP对酒精处理的NIH3T3成纤维细胞中miR-21、Smad7和转化生长因子β1基因表达的影响。酒精处理增加成纤维细胞中转化生长因子β1，至少部分是通过增加miR-21，从而抑制smad7的表达。这些效应可以通过用SFP激活NRF2来减弱。
We previously demonstrated that chronic alcohol ingestion augments TGFβ1 expression in the lung fibroblast and increases the risk of fibroproliferative disrepair in a mouse model of acute lung injury. The effect of alcohol on TGFβ1 is mitigated by treatment with sulforaphane, which can activate nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, the mechanisms by which alcohol amplifies, or SFP attenuates, TGFβ1 expression in the fibroblast are not known. MicroRNA (miR)-21 has been shown to inhibit Smad7, a TGFβ1 signaling inhibitor. In the present study, we hypothesized that alcohol augments TGFβ1 expression through up-regulation of miR-21, which subsequently inhibits Smad7. Primary mouse lung fibroblasts were cultured ± alcohol ± SFP and assessed for gene expression of miR-21, and gene and/or protein expression of Nrf2, Nrf2-regulated anti-oxidant enzymes, Smad7, STAT3, and TGFβ1. NIH 3T3 fibroblasts were transfected with a miR-21 inhibitor and cultured ± alcohol. α-SMA, Smad7, and TGFβ1 protein expression were then assessed. In parallel, NIH 3T3 lung fibroblasts were transfected with Nrf2 silencing RNA (siRNA) and cultured ± alcohol ± SFP. Gene expression of miR-21, Nrf2, Smad7, and TGFβ1 were assessed. MiR-21 gene expression was increased by 12-fold at 48 hours and Smad7 gene and protein expression were reduced by ∼30% in alcohol-treated fibroblasts. In parallel, inhibition of miR-21 attenuated alcohol-mediated decrease in Smad7 and increase in TGFβ1 and alpha-smooth muscle actin protein expression. Treatment with SFP mitigated the effect of alcohol on miR-21, Smad7, and total and phosphorylated STAT3, and restored Nrf2-regulated antioxidant gene expression. Silencing of Nrf2 prevented the effect of SFP on miR-21, Smad7, and TGFβ1 gene expression in alcohol-treated NIH 3T3 fibroblasts. Alcohol treatment increases TGFβ1 in fibroblasts, at least in part, through augmentation of miR-21, which then inhibits Smad7 expression. These effects can be attenuated by activation of Nrf2 with SFP.
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影响因子：
12.4
作者：
Chung, Arthur C. K.;Dong, Yuan;Lan, Hui Y.
通讯作者：
Lan, Hui Y.
硫烷作为针对神经退行性疾病的潜在保护性植物化学。
影响因子：
--
作者：
Tarozzi A;Angeloni C;Malaguti M;Morroni F;Hrelia S;Hrelia P
通讯作者：
Hrelia P
DOI：
10.1152/ajpgi.00019.2012
发表时间：
2012-09-01
影响因子：
4.5
作者：
Dippold, Rachael P.;Vadigepalli, Rajanikanth;Hoek, Jan B.
通讯作者：
Hoek, Jan B.
DOI：
10.1152/ajplung.00003.2004
发表时间：
2005-05-01
影响因子：
4.9
作者：
Roman, J;Ritzenthaler, JD;Guidot, D
通讯作者：
Guidot, D
影响因子：
3.2
作者：
Sueblinvong, Viranuj;Kerchberger, Vern E.;Guidot, David M.
通讯作者：
Guidot, David M.