Objective To investigate the effect of glucagon-like peptide 1 (GLP-1) receptor agonists exendin-4 on the secretion of cyclophilin A (CyPA) to inhibit atherosclerosis (AS) and vascular calcification in mice role of the process.   Methods Twenty ApoE^-/- mice were randomly divided into model group and exendin-4 group, 10 mice in each group, and were fed with high-fat diet to establish AS model, another 10 wild-type C57BL/6J mice were taken as the control group, and the exendin-4 group was intraperitoneally injected with the GLP-1R agonist exendin-4, 1/d, for 8 weeks. After 8 weeks, the ELISA method  was used to determine the level of triglyceride(TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and CyPA, serum calcium level was detected by methylthymol blue colorimetric method, oil red O staining to detect the development of atherosclerotic plaques in the aorta, HE staining was used to observe the pathological changes of the aorta, Von Kossa staining was used to observe the calcium deposition in the aorta, immunohistochemical staining, Real-time PCR and Western blotting were used to detect the expression levels of aortic RUNX2 and bone morphogenetic protein 2（BMP-2）, immunofluorescent staining was used to detect the positive expression of CyPA in aortic tissue.   Results Compared with the control group, the serum levels of TG, TC, LDL-C, Ca and CyPA in the model group increased (P<0.05), the atherosclerotic plaque areas of the aorta increased (P<0.05), the aortic wall was thickened significantly and a large number of inflammatory cells were infiltrated, a large amount of calcium deposits were deposited in the aortic parietal membrane, the positive expression area ratio of RUNX2 and BMP-2, the relative mRNA expression of RUNX2 and BMP-2, the relative protein expression of RUNX2 and BMP-2 in aortic tissue all increased (P<0.05), and the red fluorescence of CyPA expression in aortic tissue was enhanced significantly. Compared with the model group, the serum levels of TG, TC, LDL-C, Ca and CyPA in the exendin-4 group decreased (P<0.05), the atherosclerotic plaque areas of the aorta decreased (P<0.05), the thickening of the aortic wall and the infiltration of inflammatory cells were alleviated significantly, the calcium deposition in the aortic wall was reduced, the positive expression area ratio of RUNX2 and BMP-2, the relative mRNA expression of RUNX2 and BMP-2, the relative protein expression of RUNX2 and BMP-2 in aortic tissue all decreased (P<0.05), and at the same time, the red fluorescence of CyPA expression in aortic tissue was weakened significantly.   Conclusion GLP-1 receptor agonists exendin-4 can inhibit atherosclerosis and vascular calcification in mice, and the mechanism may be related to the reduction of CyPA secretion.