Arsenic trioxide eluting stent reduces neointima formation in a rabbit iliac artery injury model.
OBJECTIVE
In-stent restenosis is caused by the neointimal hyperplasia, which involves abnormal growth of vascular smooth muscle cells (VSMC). Arsenic trioxide (As2O3) is known to be a potent inhibitor of cell proliferation. We therefore studied the role of an As2O3 eluting stent in the prevention of restenosis in a rabbit iliac artery model.


RESULTS
Bare stents, or stents coated with poly-L-lactic acid (PLLA) and either 40 microg of As2O3, 180 microg of paclitaxel or vehicle were implanted into the left proximal iliac arteries of New Zealand rabbits. The delivery of drugs from stents in vitro and in vivo was evaluated by atomic fluorescence spectrophotometry and high-performance liquid chromatography, respectively. Histomorphometric measurements at 7 or 28 days showed that, comparing to rabbits receiving the PLLA stent, in animals treated with As2O3 eluting or paclitaxel eluting stent neointima thickness was reduced by 50% and 46%, the absolute neointimal area was reduced by 53% and 44%, while the absolute luminal area was increased by 46% and 43%, respectively. There were no significant differences in injury or inflammation scores among PLLA, As2O3 eluting and paclitaxel eluting stents. As2O3 eluting stent induced more TUNEL-positiv VSMC than the other stents. As2O3 levels measured in the arterial tissue were much higher than those in serum, which were nearly undetectable at 7 days after stent implantation. In in vitro studies, cultured rabbit arterial VSMC were stimulated with As2O3 or paclitaxel and analyzed for their cell cycle progression and apoptosis by flow cytometry and electron microscopy. As2O3 treatment resulted in a reduction of VSMC number in G1 phase with a concomitant increase in apoptosis of VSMC, whereas paclitaxel treatment led to blocking of VSMC in the G2/M phase.


CONCLUSIONS
In a rabbit iliac artery model PLLA coated As2O3 eluting stent significantly suppressed in-stent restenosis by reducing proliferation and inducing apoptosis of VSMC.
Yang
Wei
W
Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Ge
Junbo
J
Liu
Hongling
H
Zhao
Kan
K
Liu
Xuebo
X
Qu
Xiufen
X
Li
Weimin
W
Huang
Yonglin
Y
Sun
Aijun
A
Zou
Yunzeng
Y
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D019917:Blood Vessel Prosthesis Implantation; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D020099:Coated Materials, Biocompatible; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000627:therapeutic use*; D006965:Hyperplasia; D007083:Iliac Artery / Q000293:injuries* / Q000473:pathology / Q000601:surgery*; D008297:Male; D008855:Microscopy, Electron, Scanning; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D010087:Oxides / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use; D011817:Rabbits; D015607:Stents; D017539:Tunica Intima / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D001152:Arsenicals; D020099:Coated Materials, Biocompatible; D006131:Growth Inhibitors; D010087:Oxides; D017239:Paclitaxel; D000077237:Arsenic Trioxide