Effect of imatinib mesylate and rapamycin on the preformed intimal hyperplasia in rat carotid injury model

ABSTRACT

PURPOSE: Intimal hyperplasia (IH) is the main cause of restenosis or occlusion after vascular procedures. Imatinib mesylate and rapamycin are known to prevent IH. The purpose of this study was to evaluate the effect of these drugs on the regression of preformed IH in rat carotid injury model. METHODS: IH was established in rat carotid arteries using a balloon catheter. The drug effects were assessed in vitro on proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMC) in the neointima. And in vivo studies were carried out in 4 groups imatinib, rapamycin, combined, and no medication. After 2-week oral medication, morphometric analysis evaluated the number and density of neointimal cells, intima-to-media (I/M) ratio and cross-sectional area. Cell proliferation, apoptosis, and collagen changes were also investigated by immunohistochemical staining (IHCS). RESULTS: Imatinib and rapamycin significantly inhibited VSMC proliferation and migration, and promoted apoptosis in vitro. In morphometric analysis, the number and density of neointimal cells decreased significantly in all medication groups compared with control group (P < 0.01). However, there was no significant difference in neointimal cross-sectional area and I/M ratio among groups. In IHCS, imatinib and rapamycin inhibited neointimal cell proliferation significantly. However, there was no significant change in cell apoptosis and collagen composition. CONCLUSION: Combined treatment of with imatinib and rapamycin induced reduction of cell mass in preformed intimal hyperplasia, but failed to induce regression of intimal mass in this short-term medication study. Further studies will be needed with additional strategies of inducing lysis of the extracellular matrix.