Effect Of Simvastatin On Intimal Hyperplasia In Autogenous Vein Grafts: An Experimental Study Using A Rabbit Model

Objective: To investigate the effect of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitor, on neointimal formation in autogenous vein grafts and study the underlying mechanisms.Methods: Autogenous vein grafts model was established in 48 rabbits.Interposition jugular vein were transplaced into carotid artery of the rabbits by microsurgical technique. Animals received either simvastatin (10 mg/kg/day) or vehicle (normal saline) by oral gavage 72 hours before and then daily after surgery. Vein samples were harvested 3 days, 7 days and 28 days after operation. Intimal areas were measured using morphometric analysis of perfusion-fixed vein graft specimens, and intimal thickness was calculated using circumferential measurements. The SMC proliferation was studied by the immunohistochemical detection of proliferating cell nuclear antigen(PCNA). Expression of MMP-2,MMP-9 mRNA in vein grafts and unoperated control Vein grafts was detected by reverse transcription polymerase chain reaction (RT-PCR). Substrate gel zymography was used to determine the proteolytic activity. Immunohistochemistry technique was also used to study the expression of MMP-2 and SMCα-actin protein.Results: Intimal thickness was significantly reduced in treated animals after 7 days and 28 days by 18%,45%, respectively (P<0.05 and P<0.01). Simvastatin treatment was associated with reduced cellular proliferation(PCNA) in vein graft, and the proliferative cells were SMC conformed by SMCα-actin detection.In control group, the expression of MMP-2/MMP-9 mRNA and MMP-2 protein raised obviously after surgery, MMP-2 was widely distributed at the thickened neointima. Correspondingly, substrate gel zymography demonstrated that the proteolytic activity of MMP-2/MMP-9 was significantly increased after surgery. At 3d and 7d following surgery, simvastatin downregulated the expression of MMP-2/MMP-9 mRNA significantly in comparison with the control group (P<0.01). A remarkable decrease in proteolytic activity was noted on zymography in vein grafts from animals treated with simvastatin. The activity of MMP-2 and MMP-9 was reduced by 63% and 72%, respectively(P<0.01).Conclusion:①Simvastatin treatment can inhibit SMC proliferating effectively in vivo.②Simvastatin decrease expression and activity of MMP-2,MMP-9 in treated animals, and then inhibit migration of SMC in vein graft .③Simvastatin treatment can inhibit neointima formation, which appears to be as a result of combined inhibition of SMC proliferation and invasion.④Our results indicate that statins therapy could be useful for the prevention or treatment of vein grafts restenosis.