title: Stent-based delivery of decoy oligodeoxynucleotides against activator protein-1 binding site decreased restenosis in rabbits.
abstract: The application of drug eluting stents (DES) significantly reduced the rate of restenosis but is associated with increased risk of late stage thrombosis. Thus, development of more effective and safer drugs for in stent delivery to inhibit restenosis is of great clinical interest. Decoy oligodeoxynucleotides against activator protein-1 (AP-1) binding site (dec-ODN) delivered with one time infusion or transfer have been shown to effectively inhibit neointimal proliferation and thickening. In this study, we delivered dec-ODN against AP-1 in-stent and examined the inhibitory effects on restenosis. Synthetic dec-ODN targeting consensus AP-1 binding site was coated onto DESs. Thirty male rabbits were randomly divided into three groups: Control stent (CS), scrambled oligodeoxynucleotides (scr-ODN) stent and dec-ODN stent groups with 10 rabbits in each group. All stents were implanted in the abdominal aorta of rabbits. Eight weeks after stent implantation, the neointimal hyperplasia and re-endothelialization in the abdominal aortas of implanted segments were examined as well as the expression of TGF-beta1 and TGF-beta1 target gene connective tissue growth factor (CTGF). Dec-ODN delivered in-stent significantly inhibited the mRNA and protein expression of TGF-beta1 and CTGF, as well as neointimal thickening and restenosis in abdominal aortas as compared to control (CS) and scr-ODN. Re-endothelialization was not evidently affected by the delivery of Scr-ODN and dec-ODN. Our data demonstrate that in-stent delivery of dec-ODN against AP-1 effectively inhibited neointimal hyperplasia and support further investigation of DES/dec-ODN against AP-1 as a potential long-term therapeutic agent against in-stent restenosis.
authors.affiliation: Fujian Institute of Coronary Artery Disease and Department of Cardiology, Union Hospital Affiliated with Fujian Medical University, Fuzhou, People's Republic of China.
authors.forename: Kaimin
authors.initials: K
authors.lastname: Lin
authors.forename: Ziwen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Lianglong
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D015153:Blotting, Western; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis; D016503:Drug Delivery Systems; D054855:Drug-Eluting Stents; D004730:Endothelium, Vascular / Q000187:drug effects; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D058426:Neointima / Q000473:pathology / Q000517:prevention & control; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011817:Rabbits; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor