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Myocardin-Related Transcription Factor A Mediates LPS-Induced iNOS Transactivation

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Abstract

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-κB/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.

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Funding

This work was supported, in part, by the National Natural Science Foundation of China (No. 81870326), A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, and Six talent peaks project in Jiangsu Province.

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  1. Lin Lin and Qiumei Zhang contributed equally to this work.

Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, 1 WenYuan Road, Nanjing, 210023, China

    Lin Lin, Qiumei Zhang, Hongwei Fan, Hongwei Zhao & Yuyu Yang

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  1. Lin Lin
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  3. Hongwei Fan
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Yuyu Yang designed the study and wrote the manuscript; Lin Lin and Qiumei Zhang performed the research; Hongwei Fan and Hongwei Zhao prepared the experiment.

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Correspondence to Yuyu Yang.

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Lin, L., Zhang, Q., Fan, H. et al. Myocardin-Related Transcription Factor A Mediates LPS-Induced iNOS Transactivation. Inflammation 43, 1351–1361 (2020). https://doi.org/10.1007/s10753-020-01213-0

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