Delayed re-endothelialization with rapamycin-coated stents is rescued by the addition of a glycogen synthase kinase-3 inhibitor

Abstract

AimsDrug-eluting stents (DESs) reduce neointima area and in-stent restenosis but delay re-endothelialization. Recently, we demonstrated that pharmacological expansion and functional enhancement of endothelial progenitor cells (EPCs) can be achieved by treatment with a glycogen synthase kinase-3 inhibitor (GSKi)-even for feeble cells derived from coronary artery disease patients. GSKi treatment enhanced EPC adhesion via up-regulated expression of the-4 integrin, ameliorated re-endothelialization, and reduced neointima formation in denuded murine arteries. Hence, we hypothesized that GSKi-coated stents (GSs) will enhance EPC adhesion and attenuate delayed vascular healing associated with rapamycin, a key DES agent.Methods and resultsIn vitro human EPCs adhered to GS with affinities that were 2×, 14×, and 13× greater than vehicle (VSs)-, rapamycin (RSs)-, and rapamycin plus GSKi (RGSs)-coated stents, respectively. Stents were inserted in rabbit carotid arteries, and at 14 days, neointima area was 45 and 49 lower in GSs compared with bare metal stents (BMSs) and VSs. Moreover, RSs had a 47 larger neointima area than GSs, but RGSs reduced neointima area to a level comparable to GSs. Seven days after stenting, GSs displayed re-endothelialization that was 40, 33, and 42 greater than BMSs, VSs, and RSs, respectively. Moreover, RGSs had 41 more re-endothelialization than RSs. At 14 days, the 7-day re-endothelialization patterns persisted.ConclusionGSKi efficiently ameliorates the vascular response to stent implantation and has an important redeeming effect on the deleterious endothelial effects of rapamycin-coated stents. © The Author 2009. For permissions please.