Objective To investigate the effect of Urantide on the expression of U II and GPCR14 gene and protein in atherosclerotic heart. Methods A rat model of atherosclerosis (AS) was established by high-fat diet plus intraperitoneal injection of VD3. Rats were randomly divided into Normal group, AS group, Simvastatin group and Urantide group. Expression of U II and GPCR14 gene and protein in rat heart was measured by immunohistochemistry, qRT-PCR and Western blotting. Results Positive staining of U II and GPCR14 in AS heart tissue were increased significantly when compared with normal group (P?0.05). Quantification of U II and GPCR14 by qPCR and WB further confirmed upregulation of protein expression in AS group (P?0.05). Increased expression of U II and GPCR14 in AS group was abolished by treatment of Urantide (P?0.05). Conclusions Urantide has significant protective effect on heart in AS rats probably through downregulation of U II and GPCR14.