Sevoflurane blocks KLF5-mediated transcriptional activation of ITGB2 to inhibit macrophage infiltration in hepatic ischemia/reperfusion injury

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Journal of Gene Medicine Pub Date : 2024-05-14 DOI:10.1002/jgm.3692

Ye Li, Weinian Gao, Shuyan Lei, Xiaoning Wu, Tao Yuan, Kai Ma, Kui Chi

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引用次数: 0

Abstract

Background

Sevoflurane (Sevo) preconditioning and postconditioning play a protective role against injury induced by hepatic ischemia/reperfusion (I/R). At the same time, the involvement of macrophage infiltration in this process and the precise mechanisms are unclear. Here, we designed this research to elucidate the protective effects of Sevo against hepatic I/R injury and the molecules involved.

Methods

The alleviating effect of Sevo on the liver injury was analyzed by liver function analysis, hematoxylin and eosin staining, Masson trichrome staining, terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5′-triphosphate nick end labeling, western blot analysis and an enzyme-linked immunosorbent assay. An in vitro cell model was developed using alpha mouse liver 12 (AML12) cells, and the cell model was treated with oxygen–glucose deprivation and reoxygenation and Sevo. Multiple bioinformatics databases were used to screen transcriptional regulators related to hepatic I/R injury and the targets of Krueppel-like factor 5 (KLF5). KLF5 expression was artificially upregulated alone or with integrin beta-2 (ITGB2) knockdown to substantiate their involvement in Sevo-mediated hepatoprotection.

Results

Sevo protected the liver against I/R injury by reducing cell apoptosis and inflammatory response. KLF5 was upregulated in liver tissues following I/R injury, whereas KLF5 overexpression aggravated macrophage infiltration and liver injury induced by I/R injury. KLF5 bound to the promoter of ITGB2 to enhance ITGB2 transcription. Knockdown of ITGB2 reversed the aggravation of injury caused by KLF5 overexpression in mice and AML12 cells.

Conclusions

Sevo blocked KLF5-mediated transcriptional activation of ITGB2, thereby inhibiting macrophage infiltration in hepatic I/R injury.

Abstract Image

查看原文本刊更多论文

七氟烷可阻断KLF5介导的ITGB2转录激活，从而抑制肝缺血再灌注损伤中巨噬细胞的浸润。

背景：七氟烷（Sevo）预处理和后处理对肝缺血再灌注（I/R）引起的损伤具有保护作用。与此同时，巨噬细胞浸润在这一过程中的参与和确切机制尚不清楚。在此，我们设计了这项研究，以阐明赛沃对肝脏 I/R 损伤的保护作用及其参与分子：方法：通过肝功能分析、苏木精和伊红染色、Masson 三色染色、末端脱氧核苷酸转移酶介导的 2'-deoxyuridine 5'-triphosphate nick end 标记、Western 印迹分析和酶联免疫吸附试验分析赛沃对肝损伤的缓解作用。利用α-小鼠肝12（AML12）细胞建立了体外细胞模型，并对该细胞模型进行了氧-葡萄糖剥夺、再氧和Sevo处理。利用多个生物信息学数据库筛选与肝I/R损伤相关的转录调节因子以及Krueppel样因子5（KLF5）的靶标。为了证实KLF5参与了Sevo介导的肝脏保护作用，研究人员单独或在敲除整合素β2（ITGB2）的情况下人为上调了KLF5的表达：结果：Sevo通过减少细胞凋亡和炎症反应保护肝脏免受I/R损伤。KLF5在I/R损伤后的肝组织中上调，而KLF5的过表达会加重巨噬细胞浸润和I/R损伤引起的肝损伤。KLF5与ITGB2的启动子结合，增强了ITGB2的转录。在小鼠和AML12细胞中，敲除ITGB2可逆转KLF5过表达导致的损伤加重：Sevo阻断了KLF5介导的ITGB2转录激活，从而抑制了肝I/R损伤中巨噬细胞的浸润。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.