To investigate the effect of hirudin on vascular smooth muscle cells(VSMCs) in the rat model of hyperhomocysteine(Hcy).Methods:Fifty SD rats were randomized into a normal group，a model group and low-，medium，and high-dose(25，50，and 100 AT-U/mL) hirudin groups according to the random number table method，with 10 rats in each group.The rats in the normal group were fed with an ordinary diet.The rats in the model group and hirudin groups were fed with an ordinary diet and administrated with DL-methionine by gavage.After 21 weeks，the serum levels of 4 lipid indicators and Hcy were measured.The rats in the hirudin group were subcutaneous injected with hirudin.Two weeks later，serum lipid and Hcy levels were measured and the thoracic aorta samples were collected.Hematoxylin-eosin staining and immunohistochemical staining were employed to observe the pathological changes of the thoracic aorta and determine the expression of B-cell lymphoma-2(Bcl-2)，Bcl-2-associated X protein(Bax)，and cysteine aspartate-specific protease 3(caspase-3).Real-time fluorescence quantitative PCR was employed to determine the mRNA levels of Bcl-2，Bax，and caspase-3.Results:The hirudin groups had lower serum levels of triglyceride(TG)，total cholesterol(TC)，and low-density lipoprotein cholesterol(LDL-C)，and the high-dose hirudin group had higher serum level of high-density lipoprotein cholesterol(HDL-C)(P<0.01).The hirudin groups showed thickened aortic intima and mitigated VSMC hyperplasia.The medium- and high-dose hirudin up-regulated the protein levels of caspase-3 and Bax and down-regulated the protein level of Bcl-2 in the thoracic aorta tissue.The three doses of hirudin down-regulated the mRNA levels of Bcl-2(P<0.01)，caspase-3，and Bax，and the high-dose group demonstrated the strongest regulatory effect.Conclusion:Hirudin may delay the progression of atherosclerosis by regulating lipid metabolism and promoting the apoptosis of VSMCs with abnormal proliferation induced by Hcy.Moreover，hirudin may promote the apoptosis of VSMCs with abnormal proliferation induced by Hcy via the caspase-3/Bax/Bcl-2 signaling pathway.The study provides a new direction for the early prevention and treatment of atherosclerosis.