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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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.