关键词: 胰高血糖素样肽-1 受体, 激动剂, 高糖, 巨噬细胞, 炎症

Abstract: Objective To explore the mechanism by which the glucagon-like peptide-1 receptor (GLP-1R) agonist ( exendin-4 ) reduces the inflammation and endothelial damage induced by high glucose in macrophages. Methods Mouse monocyte macrophage leukemia cells (RAW264. 7) were divided into groups as follows: control group (RAW264. 7 cells cultured in normal medium) ; high glucose induction group (RAW264. 7 cells cultured in high glucose medium) ; exendin-4 group ( RAW264. 7 cells cultured in high glucose medium supplemented with exendin-4). The mRNA expression level of GLP-1R was detected by RT-qPCR. The mRNA expression levels of M1 pro-inflammatory factors nitric oxide synthase ( iNOS) , interleukin ( IL) -6, tumor necrosis factor ( TNF) -α ( TNF-α) and M2 specific gene IL-10, mannose receptor 1 (MRC-1) , macrophage galectin 1 ( MGL-1) , arginine-1 ( ARG-1) were also detected by RTqPCR. The expression levels of VE-cadherin, ZO-1, intercellular adhesion molecule-1 ( ICAM1) and vascular cell adhesion molecule-1 (VCAM-1) were detected by Western blotting. The expression levels of p-STAT3 and p-JNK were analyzed by Western blotting. Results  The expression level of GLP-1R mRNA was significantly decreased in the high glucose induced group compared with the control group ( P < 0. 05). The expression level of GLP-1R mRNA was significantly increased (P < 0. 05) in the exendin-4 group compared with the high glucose induction group. In the high glucose induced group relative to the control group, the expression levels of iNOS, IL-6 and TNF-α mRNA were significantly increased, and the expression levels of IL-10, MRC-1, MGL-1 and ARG-1 mRNA were significantly decreased (P < 0. 05). These indicators were significantly improved in the exendin-4 group compared with the high glucose induced group (P < 0. 05) . Compared with the control group, the expression levels of VE-cadherin and ZO-1 in the high glucose induced group were decreased, and the expression levels of ICAM-1 and VCAM-1 were increased (P < 0. 05 ) , which were significantly reversed in the exendin-4 group ( P < 0. 05 ) . Compared with the control group, the protein expression levels of p-STAT3 and p-JNK in the high glucose induced group were increased ( P < 0. 05). They were significantly decreased in the exendin-4 group when compared with the high glucose induced group (P < 0. 05). Conclusion Exendin-4 can inhibit the activation of the JNK-STAT3 pathway, promote M2 polarization and inhibit M1 polarization, reduce the expression of ICAM-1 and VCAM-1, and alleviate high glucose-induced macrophage inflammatory response.

Key words: lucagon-like peptide-1 receptor, agonist, high glucose, macrophages, inflammation, endothelial injury