AimTo investigate whether aerobic exercise could decrease plasma homocysteine (Hcy) level and reduce atherosclerosis accelerated by hyperhomocysteinemia (HHcy) in ApoE-/- mice.MethodsSix-week-old female ApoE-/- mice were assigned to three groups: control group, HHcy group and HHcy＋exercise group.HHcy animal model was made by feeding a high Hcy chow.After 1 week of acclimatization, HHcy＋exercise group was trained in a motorized rodent treadmill for 8 weeks (slope: 0°, speed: 15 m/min, 60 min/d, 5 d/wk).Plasma Hcy level and lipid levels were determined enzymatically by auto-biochemistry analysis system.Aortic roots were isolated for immunohistochemistry to compare the plaques’ areas.ResultsPlasma Hcy levels in HHcy group were higher than control group, furthermore, the Hcy levels significantly decreased in HHcy＋exercise group compared with HHcy group.There were not significant differences in body weight, daily drinking amount, plasma total cholesterol, LDLC, HDLC and triglyceride concentrations in the three groups.Compared with control group, atherosclerotic plaque area and plaque burden were increased in HHcy group.However, the plaque area and plaque burden in HHcy＋exercise group were decreased when co-mpared with HHcy group.ConclusionAerobic exercise decreases plasma Hcy levels and reduces the development of atherosclerosis in HHcy ApoE-/- mice, which does not depend on the decrease of cholesterol levels.