Myocardin-Related Transcription Factor A Mediates LPS-Induced iNOS Transactivation
Myocardin-Related Transcription Factor A Mediates LPS-Induced iNOS Transactivation
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心肌素相关转录因子 A 介导 LPS 诱导的 iNOS 反式激活
DOI：
10.1007/s10753-020-01213-0
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发表时间：
2020-05-21
期刊：
影响因子：
5.1
通讯作者：
Yang, Yuyu
中科院分区：
文献类型：
--
作者：
Lin, Lin;Zhang, Qiumei;Yang, Yuyu
巨噬细胞依赖性炎症在动脉粥样硬化形成中起关键作用。诱导型一氧化氮合酶（Inducible nitric oxide synthase，iNOS）是巨噬细胞产生的重要促炎介质之一，其水平可被脂多糖（lipopolysaccharide，LPS）上调。LPS诱导iNOS转录的表观遗传机制尚未完全阐明。我们在这里显示，肌红蛋白相关转录因子A（MRTF-A）增强了巨噬细胞中的iNOS启动子活性。由于缺乏MRTF-A，在几种细胞模型中LPS诱导的iNOS表达减少。LPS处理促进了MRTF-A的核积累及其与iNOS启动子上的NF-κ B/p65的相互作用。MRTF-A的缺乏阻止了响应于LPS处理的iNOS启动子上的活性组蛋白标记的积累。从机制上讲，MRTF-A将ASH 2（哺乳动物组蛋白H3 K4甲基转移酶复合物的关键组分）募集到iNOS启动子中。沉默ASH 2减弱LPS处理后的iNOS表达。总之，我们的数据突出了MRTF-A依赖性募集H3 K4甲基转移酶在诱导型一氧化氮合酶中的作用，并因此提供了一个新的动脉粥样硬化干预靶点。
Macrophage-dependent inflammation plays a critical role in atherogenesis. Inducible nitric oxide synthase (iNOS) is one of key pro-inflammatory mediators produced in macrophages and its levels can be upregulated by lipopolysaccharide (LPS). The epigenetic mechanism whereby LPS induces iNOS transcription is incompletely understood. We show here myocardin-related transcription factor A (MRTF-A) potentiated iNOS promoter activity in macrophages. There was a decrease in LPS-induced iNOS expression in several cell models due to the lack of MRTF-A. LPS treatment promoted nuclear accumulation of MRTF-A and its interaction with NF-kappa B/p65 on the iNOS promoter. The absence of MRTF-A prevented the accumulation of active histone marks on the iNOS promoter in response to LPS treatment. Mechanistically, MRTF-A recruited ASH2, a key component of the mammalian histone H3K4 methyltransferase complex, to the iNOS promoter. Silencing of ASH2 attenuated iNOS expression following LPS treatment. Together, our data highlight a role for MRTF-A-dependent recruitment of H3K4 methyltransferase in iNOS induction and as such provide a novel target in the intervention of atherosclerosis.