The GPR4 antagonist NE 52-QQ57 prevents ox-LDL-induced cellular senescence by promoting the expression of SIRT1.

IF 1.6 4区生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Genes & genomics Pub Date : 2025-04-10 DOI:10.1007/s13258-024-01610-x

Wei Luo, Jiming Zhou, Feng Liang, Xianghui Chou, Zhengliang Peng, Weihua Tan, Ziying Yu, Huan Wan

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引用次数: 0

Abstract

Background: Cell senescence-associated endothelia dysfunction is a vital point in the pathological progression of atherosclerosis (AS). G-protein coupled receptor 4 (GPR4) is a proton-sensing receptor involved in developing endothelial dysfunction.

Objective: In this study, we investigated the protective role of NE 52-QQ57, a GPR4 inhibitor in endothelial cell senescence induced using an oxidized low-density lipoprotein (ox-LDL). We also unravel the underlying molecular mechanism of NE 52-QQ57 as a therapeutic agent.

Methods: Endothelial cell senescence model was established using human aortic endothelial cells (HAECs) stimulated with ox-LDL. The expression levels of GPR4, p53, p16, and sirtuin1 (SIRT1) were evaluated using real-time PCR and western blot assays. ROS production was determined using dihydroethidium (DHE) staining. Further, interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) secretion and expression were determined using ELISA and real-time PCR analysis, respectively. Finally, β-galactosidase (SA-β-Gal) staining associated with cell senescence, telomerase activity, and cell cycle assay were used to determine the state of cell senescence.

Results: Firstly, GPR4 was found to be upregulated in the ox-LDL-stimulated HAECs. We also identified elevated ROS, IL-6, and MCP-1 levels induced by ox-LDL and significantly abrogated by NE 52-QQ57 treatment. Second, a reversal in SA-β-Gal activity, telomerase activity, and G0/G1 proportion, with an upregulation in p53 and p16 expressions was observed on NE 52-QQ57 treatment in the ox-LDL induced model. Lastly, the decreased expression level of SIRT1 was extremely elevated by NE 52-QQ57. Notably, the inhibitory effect of NE 52-QQ57 against ox-LDL-induced cell senescence was abolished by the SIRT1 inhibitor EX-527.

Conclusion: The GPR4 antagonist NE 52-QQ57 might prevent cellular senescence by promoting the expression of SIRT1.

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GPR4拮抗剂ne52 - qq57通过促进SIRT1的表达来阻止ox- ldl诱导的细胞衰老。

背景：细胞衰老相关的内皮功能障碍是动脉粥样硬化（AS）病理进展中的一个重要点。g蛋白偶联受体4 （GPR4）是一种参与内皮功能障碍发生的质子感应受体。目的：研究GPR4抑制剂ne52 - qq57对氧化低密度脂蛋白（ox-LDL）诱导的内皮细胞衰老的保护作用。我们还揭示了ne52 - qq57作为治疗剂的潜在分子机制。方法：采用ox-LDL刺激人主动脉内皮细胞（HAECs），建立内皮细胞衰老模型。采用实时荧光定量PCR和western blot检测GPR4、p53、p16和sirtuin1 （SIRT1）的表达水平。采用双氢乙啶（DHE）染色法测定ROS的产生。采用ELISA和real-time PCR分别检测白细胞介素-6 （IL-6）和单核细胞趋化蛋白1 （MCP-1）的分泌和表达。最后，采用与细胞衰老相关的β-半乳糖苷酶（SA-β-Gal）染色、端粒酶活性和细胞周期测定测定细胞衰老状态。结果：首先，GPR4在ox- ldl刺激的haec中表达上调。我们还发现ox-LDL诱导的ROS、IL-6和MCP-1水平升高，而ne52 - qq57治疗可显著消除这一现象。其次，在ox-LDL诱导的模型中，NE 52-QQ57处理后，SA-β-Gal活性、端粒酶活性和G0/G1比例发生逆转，p53和p16表达上调。最后，ne52 - qq57使SIRT1的表达水平显著升高。值得注意的是，NE 52-QQ57对ox- ldl诱导的细胞衰老的抑制作用被SIRT1抑制剂EX-527所消除。结论：GPR4拮抗剂NE 52-QQ57可能通过促进SIRT1的表达而延缓细胞衰老。

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

Genes & genomics 生物-生化与分子生物学

CiteScore

3.70

自引率

4.80%

发文量

131

审稿时长

6-12 weeks

期刊介绍： Genes & Genomics is an official journal of the Korean Genetics Society (http://kgenetics.or.kr/). Although it is an official publication of the Genetics Society of Korea, membership of the Society is not required for contributors. It is a peer-reviewed international journal publishing print (ISSN 1976-9571) and online version (E-ISSN 2092-9293). It covers all disciplines of genetics and genomics from prokaryotes to eukaryotes from fundamental heredity to molecular aspects. The articles can be reviews, research articles, and short communications.