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EXPERIMENTAL STUDY

Decoy oligodeoxynucleotide againstactivator protein-1 reducesneointimal proliferation after coronaryangioplasty in hypercholesterolemic minipigs

Arnd B. Buchwald, MD^*,*, Andreas H. Wagner, PhD, Christian Webel^* and Markus Hecker, PhD

^* Departments of Cardiology and Pneumology, University of Goettingen, Goettingen, Germany
Department of Cardiovascular Physiology, University of Goettingen, Goettingen, Germany

Manuscript received May 4, 2001; revised manuscript received November 7, 2001, accepted November 28, 2001.

^* Reprint requests and correspondence: Dr. Arnd B. Buchwald, Department of Cardiology and Pneumology, University of Goettingen, Robert-Koch-Str. 40, 37075 Goettingen, Germany.
buchwald{at}med.uni-goettingen.de

OBJECTIVES: 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 mm² [mean ± SEM]; p < 0.05). This effect was maintained after eight weeks (neointimal area 2.04 ± 0.22 mm²; 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.

Abbreviations and Acronyms   ppET-1   AP-1   activator protein-1   C/EBP   CCAAT/enhancer binding protein   dODN   decoy oligodeoxynucleotide   ETA   endothelin A   ET-1   endothelin-1   PBS   phosphate-buffered saline   ppET-1   prepro-endothelin-1   PTCA   percutaneous transluminal coronary angioplasty   SMC   smooth muscle cell

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