Histone deacetylase inhibition downregulates collagen 3A1 in fibrotic lung fibroblasts.
Histone deacetylase inhibition downregulates collagen 3A1 in fibrotic lung fibroblasts.
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DOI：
10.3390/ijms141019605
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发表时间：
2013-09-27
影响因子：
5.6
通讯作者：
Sanders YY
中科院分区：
文献类型：
--
作者：
Zhang X;Liu H;Hock T;Thannickal VJ;Sanders YY
特发性肺纤维化（IPF）是一种致命的疾病，其特征是肺部慢性炎症和胶原蛋白过度积累。肌成纤维细胞是肺纤维化中主要产生胶原蛋白的细胞。组蛋白脱乙酰酶抑制剂 (HDACi) 可以影响基因表达，其中一些抑制剂，如辛二酰苯胺异羟肟酸 (SAHA)，已被美国 FDA 批准用于癌症治疗。在这项研究中，我们研究了 SAHA 对原代人 IPF 成纤维细胞和小鼠肺纤维化模型中胶原蛋白 III α 1 (COL3A1) 表达的影响。我们观察到，通过 RT-PCR 检测，SAHA 治疗可以在转录水平上显着降低 IPF 成纤维细胞中 COL3A1 表达的增加；通过蛋白质印迹和免疫荧光检测发现，III 型胶原蛋白水平也降低了。通过观察处理的 IPF 细胞中组蛋白 H3 和 H4 的乙酰化水平较高，验证了 SAHA 的脱乙酰化抑制剂作用。染色质免疫沉淀 (ChIP) 实验表明，SAHA 导致的 COL3A1 表达降低与抑制性染色质标记 H3K27Me3 的关联增加以及活性染色质标记 H3K9Ac 的关联减少有关。在我们的博来霉素诱导的肺纤维化小鼠模型中，通过免疫组织化学检测，SAHA 治疗组的 III 型胶原蛋白明显减少。我们的数据表明 HDACi SAHA 改变了与 COL3A1 相关的染色质，导致其表达减少。
Idiopathic pulmonary fibrosis (IPF) is a deadly disease characterized by chronic inflammation and excessive collagen accumulation in the lung. Myofibroblasts are the primary collagen-producing cells in pulmonary fibrosis. Histone deacetylase inhibitor (HDACi) can affect gene expression, and some, such as suberoylanilide hydroxamic acid (SAHA), are US FDA approved for cancer treatment. In this study, we investigated SAHA’s effects on the expression of collagen III alpha 1 (COL3A1) in primary human IPF fibroblasts and in a murine model of pulmonary fibrosis. We observed that increased COL3A1 expression in IPF fibroblasts can be substantially reduced by SAHA treatment at the level of transcription as detected by RT-PCR; collagen III protein level was also reduced, as detected by Western blots and immunofluorescence. The deacetylation inhibitor effect of SAHA was verified by observing higher acetylation levels of both histone H3 and H4 in treated IPF cells. Chromatin immunoprecipitation (ChIP) experiments demonstrated that the reduced expression of COL3A1 by SAHA is with increased association of the repressive chromatin marker, H3K27Me3, and decreased association of the active chromatin marker, H3K9Ac. In our murine model of bleomycin-induced pulmonary fibrosis, the SAHA treated group demonstrated significantly less collagen III, as detected by immunohistochemistry. Our data indicate that the HDACi SAHA alters the chromatin associated with COL3A1, resulting in its decreased expression.
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DOI：
10.1186/1755-1536-2-7
发表时间：
2009-12-15
期刊：
Fibrogenesis & tissue repair
影响因子：
--
作者：
Chen CZ;Raghunath M
通讯作者：
Raghunath M
DOI：
10.1165/rcmb.2006-0178oc
发表时间：
2007-02-01
影响因子：
6.4
作者：
Sanders, Yan Y.;Kumbla, Pallavi;Hagood, James S.
通讯作者：
Hagood, James S.
影响因子：
4.4
作者：
Ghosh, S
通讯作者：
Ghosh, S
影响因子：
8
作者：
Huang, LL;Sowa, Y;Pardee, AB
通讯作者：
Pardee, AB
影响因子：
24.3
作者：
Dancer, R. C. A.;Wood, A. M.;Thickett, D. R.
通讯作者：
Thickett, D. R.