Decoy oligodeoxynucleotide against activator protein-1 reduces neointimal proliferation after coronary angioplasty in hypercholesterolemic minipigs.
OBJECTIVE
We sought to demonstrate, in an appropriate animal model, that co-medication with a transcription factor-blocking agent limits restenosis after percutaneous transluminal coronary angioplasty (PTCA).


BACKGROUND
Enhanced synthesis in the vessel wall of endothelin-1 (ET-1), a powerful co-mitogen for vascular smooth muscle cells, appears to be one mechanism that promotes restenosis after PTCA. Deformation-induced expression of prepro-ET-1 is governed by the transcription factor, activator protein-1 (AP-1).


METHODS
An anti-AP-1 decoy oligodeoxynucleotide (dODN) strategy was devised in which the dODN-containing solution (20 nmol) was administered locally through a Dispatch catheter into the coronary arteries of hypercholesterolemic minipigs at the time of PTCA (AVE-GFX stent).


RESULTS
Treatment with an AP-1 dODN, mimicking the consensus binding site of the transcription factor, significantly reduced neointimal formation in the coronary arteries of hypercholesterolemic minipigs (n = 10 to 12), compared with vehicle-treated coronary arteries, after four weeks of follow-up (neointimal area 2.64 +/- 0.33 vs. 4.81 +/- 1.04 mm(2) [mean +/- SEM]; p < 0.05). This effect was maintained after eight weeks (neointimal area 2.04 +/- 0.22 mm(2); n = 3) and correlated with a reduction in both nuclear translocation of AP-1 and ET-1 synthesis in the vessel wall 48 h after PTCA (n = 4). In contrast, an AP-1 mutant dODN, to which the transcription factor does not bind, showed no effect on neointimal formation at either time point (n = 3 to 7). Moreover, a consensus dODN directed against CCAAT/enhancer binding protein (C/EBP), another deformation-sensitive transcription factor, did not significantly affect neointimal formation after four weeks (n = 3).


CONCLUSIONS
These findings demonstrate the feasibility, efficacy and specificity of the anti-AP-1 dODN approach to the treatment of restenosis, which principally but not exclusively targets deformation-induced ET-1 synthesis in the vessel wall. Provided that these findings can be extrapolated to the situation of patients with coronary artery disease, the observed extent of the inhibitory effect of the AP-1 dODN treatment suggests that this co-medication may greatly reduce the incidence of in-stent restenosis.
Buchwald
Arnd B
AB
Departments of Cardiology and Pneumology, University of Goettingen, Goettingen, Germany. buchwald@med.uni-goettingen.de
Wagner
Andreas H
AH
Webel
Christian
C
Hecker
Markus
M
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D006328:Cardiac Catheterization; D003324:Coronary Artery Disease / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D023903:Coronary Restenosis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000502:physiology; D005240:Feasibility Studies; D006937:Hypercholesterolemia / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D009841:Oligonucleotides / Q000627:therapeutic use*; D013556:Swine, Miniature; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology / Q000503:physiopathology*
D019332:Endothelin-1; D009841:Oligonucleotides; D018808:Transcription Factor AP-1; D014157:Transcription Factors