Objective  To observe the effect of urantide on the expression of osteopontin (OPN) and α-smooth muscle actin (α-SMA) in the heart tissue of atherosclerosis (AS) rats, and to explore its mechanism of prevention and treatment of myocardial fibrosis injury in rats.    Methods  Totally 120 3-week-old healthy male Wistar rats in SPF grade were randomly divided into six groups: control group, model group, simvastatin group, urantide (3 days, 7 days, 14 days). HE and Masson trichrome staining were used to observe the morphology of rat heart and the expression of collagen fibers. Immunohistochemistry and Western blotting were used to detect the expression of OPN and α-SMA protein.    Results   In AS model group, cardiomyocyte hypertrophy or atrophy, a large number of inflammatory cell infiltration and a small amount of foam cells were observed in the heart tissue of rats. The increase of collagen fibers and the expression of OPN and α-SMA protein in cardiac tissue were significantly higher than those in the control group. Compared with the AS model group, after urantide treatment, cardiac injury was significantly improved, and the expression of collagen fiber, OPN and α-SMA protein was decreased.    Conclusion  Urantide can inhibit the expression of OPN and α-SMA protein in the heart tissue of AS rats to alleviate myocardial fibrosis and play a protective role in the heart tissue of AS rats.