Objective To investigate the potential role of SUMO-specific protease 1 (SENP1) in the pathogenesis of atherosclerosis in mice. Methods The development of atherosclerosis in SENP1+/+ X Apoe－/－ mice (n=5) and SENP1+/－ X Apoe－/－ mice (n=4) fed with high cholesterol and high fat diet was observed with whole aorta and aorta root oil red O staining and aorta root immunohistochemical staining of macrophage marker MOMA-2. Acetylated low density lipoprotein (ac-LDL) was used to induce the formation of foam cells and oil red O staining, and the capacities of foam cell formation were compared between RAW264.7 si-ns and RAW264.7 si-SENP1. The relative expression of fatty acid-binding protein 4 (FABP4) mRNA and protein in RAW264.7 si-ns and RAW264.7 si-SENP1 was detected by Real-Time PCR and Western blotting. Results Oil red O staining indicated that after feeding with high cholesterol and high fat diet, the relative atherosclerotic lesion areas (lesion areas/total vessel areas) and aorta arch lesion areas of SENP1+/- X Apoe－/－ mice were significantly larger than those of SENP1+/+ X Apoe－/－ mice [(6.716±1.442) % vs (5.952±2.332)% and (364 249±45 838) μm² vs (273 486±158 814) μm²]. Immunohistochemical staining revealed that the macrophage area/plaque area in aorta root in SENP1+/- X Apoe－/－ mice and SENP1+/+ X Apoe－/－ mice were (41.00±0.05)% and (40.47±0.07)% respectively, and there was no significant difference between them (P=0.954). Real-Time PCR, Western blotting and oil red O staining demonstrated that FABP4 level and capacity of foam cell formation of RAW264.7 si-SENP1 were significantly higher than those of RAW264.7 si-ns. Conclusion SENP1 may suppress the expression of FABP4 and capacity of foam cell formation of macrophages, thus may inhibit the development of atherosclerosis.