Background
Recent studies suggest that drug-eluting stent (DES) is associated with increased risk of late stent thrombosis. The mechanism of late stent thrombosis is still not clear. Poor re-endothelialization by non-selective antiproliferatives released from DES may be one of the most important factors. We developed a new endothelial cell (EC)-specific proliferative, SKL-2020, which was selected as a hydrophobic wnt agonist out of 130,000 chemical libraries.
Methods & Result
SKL-2020 enhanced EC proliferation by enhancing the expression of beta-catenin and nitric oxide, but it didn���t effect on vascular smooth muscle cell (VSMC) proliferation. Moreover, the combination of SKL-2020 with rapamycin selectively suppresses VSMC and preserved EC proliferation in vitro. Spraque-Dawdley rats were subjected to right common carotid artery denudation after transplantation of osmotic pump containing vehicle, SKL-2020, rapamycin, or SKL-2020 with rapamycin. The SKL-2020 and the SKL-2020 with rapamycin group significantly increased von Wilebrand factor positive cells compared with the vehicle and the rapamycin group at 7 days. After 14 days, the SKL-2020 and the rapamycin group showed 34% and 41% reduction of neointimal area, whereas the SKL-2020 with rapamycin group showed 63% inhibition of hyperplasia compared with vehicle group.
Conclusion
A wnt agonist, SKL-2020 selectively suppresses VMSC proliferation and preserved re-endothelial cell proliferation when treated with rapamycin both in vitro and in vivo model, suggesting it may be an ideal agent for next generation DES.