Objective To investigate the possible mechanism of proline/serine rich coil protein 1 and annexin A2 (PSRC1-ANXA2) interaction to attenuate the progression of atherosclerosis. Methods To detect the PSRC1 binding proteins, RAW264.7 macrophages were divided into two groups: control group (Ad-GFP) and PSRC1 overexpression group (Ad-PSRC1), treated with ox-LDL (100 μg/ml) for 24 h after adenovirus transfection, and the PSRC1-binding proteins were detected by non-labeled quantitative macrophages. The above protein spectra were verified by co-immunoprecipitation (Co-IP) and immunofluorescence assay. To detect the effect of PSRC1 overexpression on ANXA2 secretion after ox-LDL stimulation, RAW264.7 macrophages were divided into four groups: control group, ox-LDL group, Ad-GFP+ox-LDL group and Ad-PSRC1+ox-LDL group. The levels of ANXA2 in the cultured supernatant were determined by enzyme-linked immunosorbent assay (ELISA). To detect the knockdown effect of adenovirus Ad-shANXA2 on AXNA2, RAW264.7 macrophages were divided into two groups: Ad-GFP group and Ad-shANXA2 group. The mRNA levels of ANXA2 in RAW264.7 macrophages were detected by real-time fluorescence quantitative PCR (RT-qPCR). To detect the effect of ANXA2 knockdown on the progression of aortic plaque and the secretion of inflammatory factors, 24 ApoE^-/- mice were randomly divided into four groups (6 each): chow diet+Ad-GFP group, chow diet+Ad-shANXA2 group, high fat diet+Ad-GFP group and high fat diet+Ad-shANXA2 group. The atherosclerosis areas (AS) of aorta and aortic root were detected by oil red O staining. The serum levels were determined by ELISA assay of interleukin-1β (IL-1β) and IL-6 in high fat diet+Ad-GFP group and high fat diet+Ad-shANXA2 group. Results The results of proteomics analysis showed that, after stimulation with ox-LDL, the binding of PSRC1 and ANXA2 increased significantly, and the combination was of specificity. Immunofluorescence also showed that the co-localization of PSRC1 and ANXA2 existed in the cells. RT-PCR revealed that, compared with Ad-GFP group, the ANXA2 level decreased significantly in Ad-shANXA2 group (0.198±0.065 vs. 1.002±0.069, P<0.05). ELISA results showed that, compared with the control group, the ANXA2 level increased significantly in the ox-LDL group [(2027.23±93.55) pg/ml vs. (697.01±30.08) pg/ml, P<0.01], and compared with Ad-GFP+ox-LDL group, the ANXA2 level reduced significantly in Ad-PSRC1+ox-LDL group [(1061.65±68.52) pg/ml vs. (2098.67±318.41) pg/ml, P<0.01]. In animal experiments, oil red O staining revealed that no statistical difference existed in the area of aortic gross and aortic root plaques between the two groups of chow diet.Compared with high-fat diet+Ad-GFP group, the percentage of aortic plaque area decreased significantly, and of aortic root section also decreased significantly in high-fat diet+Ad-shANXA2 group (5.29%±1.14% vs. 12.28%±2.48%, P<0.05; 1.31%±0.04%vs. 2.83%±0.22%, P<0.05). ELISA test found that, compared with high-fat diet+Ad-GFP group, the IL-1β level decreased significantly [(122.90±9.80) pg/ml vs. (172.90±21.83) pg/ml, P<0.05], and the IL-6 level decreased also [(3.65±0.12) pg/ml vs.(5.97±0.42) pg/ml, P<0.05] in high-fat diet+Ad-shANXA2 group. Conclusion Over-expression of PSRC1 in macrophages can attenuate the progression of atherosclerosis, where the increased binding of PSRC1 to ANXA2, and the inhibition of ANXA2 release, thereby inhibiting the release of inflammatory factor may be the possible related mechanism.