Systemic Delivery of Clopidogrel Inhibits Neointimal Formation in a Mouse Vein Graft Model

Abstract

Clopidogrel inhibits platelet aggregation and has beneficial effects on patients undergoing coronary artery bypass grafting surgery, but it is unknown whether clopidogrel inhibits the neointima formation of grafted veins. In this study, we used a murine vein graft model to study the effect of clopidogrel on intima hyperplasia of the vein graft. Vein grafting was performed among C57BL/6J mice, immediately after surgery; 1 mg/kg clopidogrel and vehicle control were used to inject mice peritoneally daily for 2 weeks. As compared with the vehicle, clopidogrel significantly inhibited the neointima formation of vein grafts at 4 weeks after surgeries. The immunohistochemistry study showed that as compared with the vehicle, clopidogrel significantly decreased the rate of proliferating cell nuclear antigen-positive cells in the wall of vein grafts and significantly increased the expression of vascular smooth muscle cell (VSMC) contractile protein markers (α-smooth muscle actin, calponin, and SM22) within the neointima area of vein grafts. Clopidogrel significantly decreased the plasma interleukin 6 (IL-6) level at 1 week after surgery as compared with the vehicle. We isolated VSMCs from mouse aortic arteries. As compared with the vehicle, clopidogrel significantly inhibited thrombin-induced VSMC proliferation and migration, significantly decreased IL-6 mRNA expression and protein secretion, and increased intracellular cyclic adenosine monophosphate generation in a dose-dependent manner. In conclusion, systemic delivery of clopidogrel inhibits neointima formation of the mouse vein graft, the mechanisms of which are associated with its inhibitory effects on VSMC proliferation, migration, and the tendency to synthetic phenotype after vein graft surgery, reducing the expression of IL-6 and increasing the intracellular cyclic adenosine monophosphate level.