Synergistic Suppression of Rat Neointimal Hyperplasia by Rapamycin and Imatinib Mesylate: Implications for the Prevention of Accelerated Arteriosclerosis

Abstract

Background: Accelerated arteriosclerosis remains a major limitation to therapeutic interventions such as angioplasty, stent deployment, and solid organ transplantation. Rapamycin, a powerful new immunosuppressant set to replace calcineurin inhibitors in the transplant setting, and imatinib mesylate, a receptor tyrosine kinase inhibitor, are both angioprotective. Here, we explored the pharmacological and therapeutic interactions of these two agents in a rat model of neointimal hyperplasia. Methods: Wistar rats, subjected to balloon catheter-induced aortic injury, received daily drug treatment until postoperative day 14 and were subsequently sacrificed or followed up to day 40 without further treatment. Development of neointimal lesions was assessed histologically and immunohistochemically. Steady-state rapamycin levels in whole blood were determined by HPLC-UV. Results: Rapamycin and imatinib, administered individually or in combination, produced no signs of overt toxicity. Continuous postoperative therapy with either rapamycin (0.5–1.5 mg/kg/day) or imatinib (2– 50 mg/kg/day) dose-dependently suppressed neointimal hyperplasia on day 14. Combined treatment (0.5 or 1 + 10 mg/kg/day, respectively) showed a trend towards synergistic action on day 14. Withdrawal of medication on day 14 nullified the early therapeutic effect of either agent by day 40. In contrast, early combination therapy (1 + 10 mg/kg/day) achieved long-term suppression of neointimal hyperplasia by approximately 81%. Notably, coadministration of imatinib appeared to reduce exposure to rapamycin, although this finding did not reach statistical significance. Conclusions: Short-term combination therapy with rapamycin and imatinib is well tolerated and produces synergistic, sustained suppression of neointimal hyperplasia in rats. Subject to clinical evaluation, this new drug regimen may afford definitive prophylaxis against accelerated arteriosclerosis.

Mechanisms behind the Synergistic Effect of Sirolimus and Imatinib in Preventing Restenosis after Intimal Injury

“…As in our previous study [14], the treatments were well tolerated. Cardiac, gastric, enteric, hepatic and renal histology were previously shown to be normal [14].…”

“…Cardiac, gastric, enteric, hepatic and renal histology were previously shown to be normal [14]. In this study, there were no significant weight differences between treatment groups and no signs of adverse effects from the treatments such as delayed wound healing, diarrhea, overall sickness behavior or hair loss (data not shown).…”

“…for 14 days is well tolerated and produces synergistic suppression of rat neointimal hyperplasia that persists until day 40 after injury [14]. In the present study, we extended the follow-up period to 90 days to determine the long-term efficacy of this combination therapy.…”

“…The rats were treated with previously established submaximal doses of (1) sirolimus 1.0 mg/kg/day, (2) imatinib 10.0 mg/kg/day, (3) a combination of these, or (4) vehicle [14]. Treatment was initiated 3 days before the operation and continued until 14 days after the injury.…”

“…We have recently reported a synergistic effect between sirolimus and imatinib in the prevention of restenosis after balloon injury in rats, lasting up to 40 days after injury [14]. The synergy was seen already at well-tolerated submaximal doses of the drugs.…”