Abstract 3951: Glycogen Synthase Kinase 3 Beta Inhibitor Coated Stents Inhibit Neointimal Formation and Enhance Re-endothelialization Through Improved Endothelial Progenitor Cell Recruitment and Function
Background: Drug eluting stents reduce neointimal growth and revascularization rates but with a clinically relevant delay in reendothelialization (RE). Recently, we demonstrated that pharmacological expansion and functional enhancement of endothelial progenitor cell (EPC) can be achieved by treatment with a glycogen synthase kinase 3-beta inhibitor (GSKI). Dose dependant GSKI-related improvements in EPC yield and cell survival were even seen in cells from patients with CAD and in part were related to a reduction in apoptosis. Moreover, GSKI treatment enhanced EPC adhesion via the upregulation of the α-4 integrin subunit.
Purpose: We hypothesize that local delivery of GSKI by drug coated stents may result in enhanced arterial repair.
Methods / Results: First we studied the in vitro effects of drug coating on EPC attachment to stents. Human EPCs were cultured in the presence of one of the following coated stents: vehicle (VCS), GSKI (GCS), and rapamycin (RCS). Notably, there was a 20-fold increase in EPC attachment to GCSs compared to RCSs and a 2-fold increase compared to VCSs (21.5 ± 2.7 vs 1.5 ± 0.8 vs 10.2 ± 1.6, p<0.05). Second, we examined the effects of local (stent-based) delivery of GSKI using a previously described rabbit carotid stenting model. Bare metal stents (BMSs), VCSs, GCSs, or RCSs were examined for RE 7 days post stent implantation. Using scanning electron microscopy we noted a marked increase in RE with GCSs compared to BMSs and VCSs respectively (65.6 ± 6.4% vs 46.7 ± 3.8% vs 49.4 ± 3.2%, p<0.05). Similarly, coating stents with both GSKI and rapamycin improved RE (63.0 ± 4.5%; p<0.05 compared to rapamycin alone). At 14 days, GCSs also demonstrated a reduction in neointima formation by 48.4% relative to VCS and BMS (p<0.05). Finally, there was a 4-fold increase in EPC colony forming capacity in rabbits with GCS implantation compared to rabbits that received VCSs or BMSs (p<0.05).
Conclusion: Inhibition of GSK-3β by means of a GSKI coated stent provides a novel strategy for the augmentation of EPC recruitment and RE post-stent implantation. These data provide a therapeutic foundation for improving the clinical safety of drug eluting stents.