GOLM1 Promotes Atherogenesis by Activating Macrophage EGFR-ERK Signaling Cascade.

IF 16.5 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation research Pub Date : 2025-03-03 DOI:10.1161/CIRCRESAHA.124.325880

Xiaochen Gai, Fangming Liu, Yixin Chen, Baohui Zhang, Yinliang Zhang, Yuting Wu, Shuhui Yang, Linlin Chen, Weiwei Deng, Yuan Wang, Shuiyun Wang, Cuntao Yu, Jie Du, Zhengyi Zhang, Jing Wang, Hongbing Zhang

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引用次数: 0

Abstract

Background: Atherosclerosis is a chronic inflammatory disease. GOLM1 (Golgi membrane protein 1) is an inflammation-responsive protein and a mediator in some inflammation-associated pathological processes. Because we found a positive correlation between GOLM1 expression and atherosclerosis progression by checking the gene expression data set of human atherosclerotic lesions, we explored the potential significance of GOLM1 in atherosclerosis in this study.

Methods: GOLM1 levels in serums and lesions of patients with atherosclerosis and mice with atherosclerosis were examined by immunostaining and ELISA. Gain-of-function and loss-of-function approaches were used to study the impacts of GOLM1 in inflammation and atherogenesis of Apoe^-/- mice on a Western diet. The effects of GOLM1 on macrophage behaviors were determined by OxLDL (oxidized low-density lipoprotein) uptake assay, single-cell sequencing analysis, global phosphoproteomics analysis, and molecular biological techniques. The therapeutic potential of GOLM1 neutralization for atherosclerosis was evaluated in Apoe^-/- mice.

Results: GOLM1 was elevated in serums and lesions of patients with atherosclerosis and mice with atherosclerosis. Global deletion of GOLM1 ameliorated mouse inflammation and atherosclerosis, while knock-in of GOLM1 exacerbated these pathological manifestations. Furthermore, hepatic GOLM1 deletion reduced circulating GOLM1 and attenuated atherogenesis. Mechanistically, the expression and secretion of GOLM1 were induced in multiple mouse tissues by atherogenic stimulus, leading to the elevation of extracellular GOLM1. Extracellular GOLM1 then stimulated ERK (extracellular signal-regulated kinase) signaling cascade by binding to its putative receptor EGFR (epidermal growth factor receptor) to promote macrophage uptake of LDL (low-density lipoprotein) and enhance the corresponding macrophage immune response. Moreover, neutralizing GOLM1 by an antibody suppressed mouse inflammation and atherogenesis.

Conclusions: GOLM1 is an atherogenic mediator and a promising therapeutic target for the intervention of atherosclerotic diseases.

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GOLM1通过激活巨噬细胞EGFR-ERK信号级联促进动脉粥样硬化。

背景：动脉粥样硬化是一种慢性炎症性疾病。GOLM1（高尔基膜蛋白1）是一种炎症反应蛋白，在一些炎症相关的病理过程中起中介作用。由于我们通过检查人类动脉粥样硬化病变基因表达数据集发现GOLM1表达与动脉粥样硬化进展呈正相关，因此我们在本研究中探讨了GOLM1在动脉粥样硬化中的潜在意义。方法：采用免疫染色法和ELISA法检测动脉粥样硬化患者及动脉粥样硬化小鼠血清及病变组织中GOLM1水平。采用功能获得和功能丧失的方法研究了GOLM1对Apoe-/-小鼠在西方饮食中的炎症和动脉粥样硬化的影响。GOLM1对巨噬细胞行为的影响通过OxLDL（氧化低密度脂蛋白）摄取试验、单细胞测序分析、全局磷酸化蛋白质组学分析和分子生物学技术来确定。在Apoe-/-小鼠中评估了GOLM1中和对动脉粥样硬化的治疗潜力。结果：动脉粥样硬化患者及小鼠血清及病变中GOLM1升高。GOLM1的整体缺失改善了小鼠的炎症和动脉粥样硬化，而GOLM1的敲入加重了这些病理表现。此外，肝脏GOLM1缺失减少了循环GOLM1并减轻了动脉粥样硬化的发生。在机制上，通过致动脉粥样硬化刺激诱导多种小鼠组织中GOLM1的表达和分泌，导致细胞外GOLM1升高。然后，细胞外GOLM1通过与其假定的受体表皮生长因子受体（EGFR）结合，刺激ERK（细胞外信号调节激酶）信号级联，促进巨噬细胞摄取LDL（低密度脂蛋白），增强相应的巨噬细胞免疫应答。此外，通过抗体中和GOLM1可抑制小鼠炎症和动脉粥样硬化。结论：GOLM1是一种动脉粥样硬化介质，是介入动脉粥样硬化疾病的有希望的治疗靶点。

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

Circulation research 医学-外周血管病

CiteScore

29.60

自引率

2.00%

发文量

535

审稿时长

3-6 weeks

期刊介绍： Circulation Research is a peer-reviewed journal that serves as a forum for the highest quality research in basic cardiovascular biology. The journal publishes studies that utilize state-of-the-art approaches to investigate mechanisms of human disease, as well as translational and clinical research that provide fundamental insights into the basis of disease and the mechanism of therapies. Circulation Research has a broad audience that includes clinical and academic cardiologists, basic cardiovascular scientists, physiologists, cellular and molecular biologists, and cardiovascular pharmacologists. The journal aims to advance the understanding of cardiovascular biology and disease by disseminating cutting-edge research to these diverse communities. In terms of indexing, Circulation Research is included in several prominent scientific databases, including BIOSIS, CAB Abstracts, Chemical Abstracts, Current Contents, EMBASE, and MEDLINE. This ensures that the journal's articles are easily discoverable and accessible to researchers in the field. Overall, Circulation Research is a reputable publication that attracts high-quality research and provides a platform for the dissemination of important findings in basic cardiovascular biology and its translational and clinical applications.