on March 26, 2009
Published online before print March 26, 2009, doi: 10.1161/ATVBAHA.109.186429
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Submitted on October 9, 2008
Accepted on March 9, 2009
Human Placental Ectonucleoside Triphosphate Diphosphohydrolase Gene Transfer via Gelatin-Coated Stents Prevents In-Stent Thrombosis
Yasuhiro Takemoto ;
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.
* To whom correspondence should be addressed. 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.
Key words: cationic gelatin • E-NTPDase • gene therapy • thrombosis • platelets