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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:857.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Human Placental Ectonucleoside Triphosphate Diphosphohydrolase Gene Transfer via Gelatin-Coated Stents Prevents In-Stent Thrombosis

Yasuhiro Takemoto; Hiroyuki Kawata; Tsunenari Soeda; Keiichi Imagawa; Satoshi Somekawa; Yukiji Takeda; Shiro Uemura; Masanori Matsumoto; Yoshihiro Fujimura; Jun-ichiro Jo; Yu Kimura; Yasuhiko Tabata; Yoshihiko Saito

From the First Department of Internal Medicine (Y.T., H.K., T.S., K.I., S.S., Y.T., S.U., Y.S. and Blood Transfusion Medicine (M.M., Y.F.), Nara Medical University, Japan; and the Department of Biomaterials (U.J., Y.K., Y.T.), Field of Tissue Engineering, Kyoto University, Kyoto, Japan.

Correspondence to Hiroyuki Kawata, MD, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. E-mail hkawata{at}naramed-u.ac.jp

Background— In-stent thrombosis is mainly triggered by adenosine diphosphate (ADP)-dependent platelet aggregation after percutanous coronary stent implantation. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) rapidly hydrolyzes ADP to adenosine monophosphate, inhibiting platelet aggregation. We tested the hypothesis that local delivery of human placental E-NTPDase (pE-NTPDase) gene into injured arteries via gene-eluting stent could prevent subacute in-stent thrombosis.

Methods and Results— We generated gene-eluting stents by coating bare metal stents with cationic gelatin hydrogel containing pE-NTPDase cDNA (pE-NTPDase stent), and implanted the stents into rabbit femoral arteries (FA) prone to production of platelet-rich thrombi due to repeated balloon injury at 4-week intervals. After the second injury, E-NTPDase gene expression was severely decreased; however, the implantation of pE-NTPDase stent increased E-NTPDase mRNA levels and NTPDase activity to higher level than normal FA. The FAs with pE-NTPDase stents maintained patency in all rabbits (P<0.01), whereas the stent-implanted FAs without pE-NTPDase gene showed low patency rates (17% to 25%). The occlusive platelet-rich thrombi, excessive neointimal growth, and infiltration of macrophages were inhibited in stent implanted FA with pE-NTPDase gene, but not without pE-NTPDase gene.

Conclusions— Human pE-NTPDase gene transfer via cationic gelatin-coated stents inhibited subacute in-stent thrombosis and suppressed neointimal hyperplasia and inflammation without antiplatelet drugs.

In the present study, we generated a new type of gene-eluting stent for the purpose of preventing in-stent thrombosis. Our results suggested that human placental E-NTPDase gene transfer via cationic gelatin-coated stents inhibited platelet aggregation by providing the enhanced E-NTPDase expression and preserved local NTPDase activity, thereby preventing in-stent thrombosis.

Key Words: cationic gelatin • E-NTPDase • gene therapy • thrombosis • platelets