Oral everolimus inhibits intimal proliferation in injured carotid artery in rats

Abstract

Background Everolimus, a derivative of sirolimus, is a potent immunosuppressant that has important anti-proliferative properties. In the present study, we demonstrated the inhibiting neointimal hyperplasia in injured carotid arteries in rats by using two different doses of everolimus administrated via the oral route for a long time. Methods A rat model of carotid artery injury was established by balloon inflation. Eighty rats were randomly divided into the sham-operated group (n=20), injury group (n=20), low dosage of everolimus group (n=20), and high dosage of everolimus group (n=20). The low dose of everolimus (1.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 0.75 mg/kg per day for 28 days via intragastric gavage. High dose everolimus (2.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 1 mg/kg per day for 28 days. Expression of eukaryotic translation initiation factor 4E (eIF-4E) and phosphorylation of ribosomal protein S6 kinase 1 (P70S6K) were determined by reverse transcription-polymerase chain reaction and Western blotting analysis. Results In the injured carotid artery, neointimal hyperplasia was normally observed four weeks after injury. Everolimus inhibited neointimal hyperplasia after balloon injury in a dose dependent manner. At the same time, the study demonstrated that everolimus reduced the expression of P-P70S6K, eIF-4E, transforming growth factor (TGF)-β1 and of proliferating cell nuclear antigen (PCNA). Conclusions Everolimus significantly inhibited neointimal hyperplasia of the injured carotid artery. The effect depended on dosage and was associated with the reduction of phosphorylation of P70S6K and the eIF-4E expression level.