[ATF3 regulates inflammatory response in atherosclerotic plaques in mice through the NF-κB signaling pathway].

Q3 Medicine
Bing Xia, Jin Peng, Jiuyang Ding, Jie Wang, Guowei Tang, Guojie Liu, Yun Wang, Changwu Wan, Cuiyun LE
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引用次数: 0

Abstract

Objectives: To investigate the role of activating transcription factor 3 (ATF3) in atherosclerotic plaques for regulating inflammatory responses during atherosclerosis (AS) progression.

Methods: Human coronary artery specimens from autopsy cases were examined for ATF3 protein expression and localization using immunofluorescence staining and Western blotting. Apolipoprotein E-deficient (ApoE-/-) mouse models of AS induced by high-fat diet (HFD) feeding for 12 weeks were subjected to tail vein injection of adeno-associated virus serotype 9 (AAV9) to knock down ATF3 expression. After an additional 5 weeks of HFD feeding, the mice were euthanized for analyzing structural changes of the aortic plaques, and the expression levels of ATF3, inflammatory factors (CD45, CD68, IL-1β, and TNF-α), and NF-κB pathway proteins (P-IKKα/β and P-NF-κB p65) were detected. In the cell experiment, THP-1-derived foam cells were transfected with an ATF3-overexpressing plasmid or an ATF3-specific siRNA to validate the relationship between ATF3 and NF‑κB signaling.

Results: In human atherosclerotic plaques, ATF3 expression was significantly elevated and partially co-localized with CD68. ATF3 knockout in ApoE-/- mice significantly increased aortic plaque volume, upregulated the inflammatory factors, enhanced phosphorylation of the NF‑κB pathway proteins, and increased the expressions of VCAM1, MMP9, and MMP2 in the plaques. In THP-1-derived foam cells, ATF3 silencing caused activation of the NF‑κB pathway, while ATF3 overexpression suppressed the activity of the NF-κB pathway.

Conclusions: AS promotes ATF3 expression, and ATF3 deficiency exacerbates AS progression by enhancing plaque inflammation via activating the NF-κB pathway, suggesting the potential of ATF3 as a therapeutic target for AS.

[ATF3通过NF-κB信号通路调节小鼠动脉粥样硬化斑块的炎症反应]。
目的:探讨激活转录因子3 (ATF3)在动脉粥样硬化斑块中调节动脉粥样硬化(AS)进展过程中炎症反应的作用。方法:采用免疫荧光染色和Western blotting检测尸检病例人冠状动脉标本中ATF3蛋白的表达和定位。采用高脂饮食(HFD)喂养12周的载脂蛋白e缺陷(ApoE-/-) AS小鼠模型,通过尾静脉注射血清型9型腺相关病毒(AAV9)来降低ATF3的表达。再饲喂HFD 5周后,将小鼠安乐死,分析主动脉斑块的结构变化,并检测ATF3、炎症因子(CD45、CD68、IL-1β和TNF-α)和NF-κB通路蛋白(P-IKKα/β和P-NF-κB p65)的表达水平。在细胞实验中,用过表达ATF3的质粒或ATF3特异性siRNA转染thp -1衍生的泡沫细胞,验证ATF3与NF - κB信号传导之间的关系。结果:在人类动脉粥样硬化斑块中,ATF3的表达显著升高,并与CD68部分共定位。敲除ApoE-/-小鼠的ATF3显著增加主动脉斑块体积,上调炎症因子,增强NF - κB通路蛋白磷酸化,增加斑块中VCAM1、MMP9和MMP2的表达。在thp -1来源的泡沫细胞中,ATF3沉默引起NF-κB通路的激活,而ATF3过表达抑制NF-κB通路的活性。结论:AS促进ATF3表达,ATF3缺乏通过激活NF-κB通路增强斑块炎症从而加剧AS进展,提示ATF3可能作为AS的治疗靶点。
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
南方医科大学学报杂志
南方医科大学学报杂志 Medicine-Medicine (all)
CiteScore
1.50
自引率
0.00%
发文量
208
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