Inhibition of HMGN2 SUMOylation ameliorates atherosclerosis by activating PAX5 expression to induce macrophage M2 polarization

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Xiangkui Wang , Peipei Wu , Yadi Shen , Shiwei Xu , Qi Wan , Yongfei Yang
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引用次数: 0

Abstract

Background

As a core pathological process of cardiovascular disease, atherosclerosis (AS) progression is closely linked to macrophage polarization, yet the mechanisms by which post-translational modifications regulate inflammatory responses in AS remain unclear.

Methods

Using oxidized low-density lipoprotein (ox-LDL)-induced RAW264.7 foam macrophages and high-fat diet-fed (apolipoprotein E knockout) ApoE−/− mice, we assessed HMGN2 SUMOylation's role in macrophage M2 polarization. Cell proliferation/migration were analyzed via EdU/Transwell assays; macrophage polarization phenotypes were examined by immunofluorescence. Inflammatory cytokines and NF-κB pathway were quantified using ELISA/Western blot. Aortic plaque formation and lipid deposition were evaluated through HE staining and Oil Red O lipid visualization.

Results

In cellular experiments, research demonstrated that HMGN2 enhances interaction with the transcription factor PAX5 through SUMOylation, thereby inhibiting PAX5 activity and driving macrophage polarization toward the pro-inflammatory M1 phenotype. Furthermore, PIAS1 knockdown significantly reduced HMGN2 SUMOylation levels. This disruption suppressed the binding between PAX5 and HMGN2 and reduced inflammatory factor release. Animal experiments revealed that targeted PIAS1 knockdown markedly reduced aortic plaque area, improved lipid metabolic disorders, and modulated inflammatory cytokines by inhibiting NF-κB signaling pathway.

Conclusion

The present study systematically reveals the molecular mechanism by which HMGN2 SUMOylation regulates macrophage polarization and inflammatory response through the "PAX5-NF-κB" signaling axis, which may become a new target for the treatment of atherosclerosis by targeting epigenetic modification.
抑制HMGN2 summoylation通过激活PAX5表达诱导巨噬细胞M2极化来改善动脉粥样硬化
作为心血管疾病的核心病理过程,动脉粥样硬化(AS)的进展与巨噬细胞极化密切相关,但翻译后修饰调节AS炎症反应的机制尚不清楚。方法利用氧化低密度脂蛋白(ox-LDL)诱导的RAW264.7泡沫巨噬细胞和高脂饮食喂养(载脂蛋白E敲除)ApoE - / -小鼠,我们评估了HMGN2 summoylation在巨噬细胞M2极化中的作用。通过EdU/Transwell分析细胞增殖/迁移;免疫荧光法检测巨噬细胞极化表型。采用ELISA/Western blot法定量检测炎症因子和NF-κB通路。通过HE染色和油红O脂质可视化观察主动脉斑块形成和脂质沉积情况。结果在细胞实验中,研究表明HMGN2通过SUMOylation增强与转录因子PAX5的相互作用,从而抑制PAX5活性,驱动巨噬细胞向促炎M1表型极化。此外,PIAS1敲低显著降低HMGN2 summoylation水平。这种破坏抑制了PAX5和HMGN2之间的结合,减少了炎症因子的释放。动物实验发现,靶向敲低PIAS1可显著减少主动脉斑块面积,改善脂质代谢紊乱,并通过抑制NF-κB信号通路调节炎症细胞因子。结论本研究系统揭示了HMGN2 summoylation通过“PAX5-NF-κB”信号轴调控巨噬细胞极化和炎症反应的分子机制,可能成为靶向表观遗传修饰治疗动脉粥样硬化的新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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