Delayed re-endothelialization with rapamycin-coated stents is rescued by the addition of a glycogen synthase kinase-3beta inhibitor.
OBJECTIVE
Drug-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-3beta inhibitor (GSKi)-even for feeble cells derived from coronary artery disease patients. GSKi treatment enhanced EPC adhesion via up-regulated expression of the alpha-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.


RESULTS
In vitro human EPCs adhered to GS with affinities that were 2x, 14x, and 13x 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.


CONCLUSIONS
GSKi efficiently ameliorates the vascular response to stent implantation and has an important redeeming effect on the deleterious endothelial effects of rapamycin-coated stents.
Ma
Xiaoli
X
Vascular Biology Laboratory, Division of Cardiology, University of Ottawa Heart Institute, Room H-2263, Ottawa, ON, Canada K1Y4W7.
Hibbert
Benjamin
B
Dhaliwal
Bharbhoor
B
Seibert
Tara
T
Chen
Yong-Xiang
YX
Zhao
Xiaoling
X
O'Brien
Edward R
ER
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054855:Drug-Eluting Stents; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008297:Male; D011474:Prosthesis Design; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D020123:Sirolimus / Q000494:pharmacology*; D013234:Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013997:Time Factors
D047428:Protein Kinase Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D020123:Sirolimus