GOLM1 Promotes Atherogenesis by Activating Macrophage EGFR-ERK Signaling Cascade

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.

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.

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.

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