Nrf2 attenuates the innate immune response after experimental myocardial infarction
Nrf2 attenuates the innate immune response after experimental myocardial infarction
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DOI：
10.1101/2022.01.10.475615
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发表时间：
2022-01
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通讯作者：
D. Bromage;S. Trevelin;Josef Huntington;Victoria X Yang;Ananya Muthukumar;Sarah Mackie;G. Sawyer;Xiaohong Zhang;Celio X. C. Santos;N. Safinia;I. Smyrnias;M. Giacca;Alex Ivetic;A. Shah
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作者：
D. Bromage;S. Trevelin;Josef Huntington;Victoria X Yang;Ananya Muthukumar;Sarah Mackie;G. Sawyer;Xiaohong Zhang;Celio X. C. Santos;N. Safinia;I. Smyrnias;M. Giacca;Alex Ivetic;A. Shah
目的探讨转录因子核因子红细胞衍生2-样2（Nrf 2）在实验性心肌梗死（MI）后炎症反应中的作用。研究背景：有令人信服的证据表明，心肌梗死后心室重构和心力衰竭（HF）的机制中存在炎症失调。转录因子Nrf 2（由Nfe 2l 2编码）是在这种情况下有希望的靶标。它阻碍促炎细胞因子的转录上调，并在各种鼠模型中具有抗炎作用。方法我们对Nrf 2-/-小鼠和野生型（WT）对照进行永久性左冠状动脉（LCA）结扎。用外周血和心脏细胞悬液的荧光激活细胞分选（FACS）分析以及梗死组织的趋化因子及其受体的qRT-PCR研究炎症反应。为了研究Nrf 2介导的转录是否是白细胞的专用功能，我们在永久性LCA连接Nrf 2调节基因（NRG）表达后询问了小鼠心脏的公开可用RNA测序（RNA-seq）数据。结果与WT小鼠相比，在MI后，FACS分析显示在全局Nrf 2-/-小鼠的心脏中有深度发炎的表型。此外，来自Nrf 2-/-小鼠的梗死组织显示炎性细胞因子、趋化因子及其受体（包括IL 6、Ccl 2和Cxcr 4）的较高表达。RNA-seq分析显示，与未处理的小鼠相比，MI后WT小鼠中的NRG表达上调，这在生物信息学分离的CCR 2+细胞中显著更高。总之，结果表明，白细胞中的Nrf 2信号传导，以及可能的CCR 2+单核细胞衍生的心脏驻留巨噬细胞，可能是预防MI后心室重构的潜在靶点。
Objectives We aimed to investigate the contribution of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) to the inflammatory response after experimental myocardial infarction (MI). Background There is compelling evidence implicating dysregulated inflammation in the mechanism of ventricular remodeling and heart failure (HF) after MI. The transcription factor Nrf2 (encoded by Nfe2l2) is a promising target in this context. It impedes transcriptional upregulation of pro-inflammatory cytokines and is anti-inflammatory in various murine models. Methods We subjected Nrf2-/- mice and wild type (WT) controls to permanent left coronary artery (LCA) ligation. The inflammatory response was investigated with fluorescence-activated cell sorting (FACS) analysis of peripheral blood and heart cell suspensions, together with qRT-PCR of infarcted tissue for chemokines and their receptors. To investigate whether Nrf2-mediated transcription is a dedicated function of leukocytes, we interrogated publicly available RNA-sequencing (RNA-seq) data from mouse hearts after permanent LCA ligation for Nrf2-regulated gene (NRG) expression. Results FACS analysis demonstrated a profoundly inflamed phenotype in the hearts of global Nrf2-/- mice as compared to WT mice after MI. Moreover, infarcted tissue from Nrf2-/- mice displayed higher expression of inflammatory cytokines, chemokines, and their receptors, including IL6, Ccl2, and Cxcr4. RNA-seq analysis showed upregulated NRG expression in WT mice after MI compared to untreated mice, which was significantly higher in bioinformatically isolated CCR2+ cells. Conclusions Taken together, the results suggest that Nrf2 signalling in leukocytes, and possibly CCR2+ monocyte-derived cardiac resident macrophages, may be potential targets to prevent post-MI ventricular remodeling.