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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:949.)
© 2002 American Heart Association, Inc.

Vascular Biology

CCAAT/Enhancer-Binding Protein Decoy Oligodeoxynucleotide Inhibition of Macrophage-Rich Vascular Lesion Formation in Hypercholesterolemic Rabbits

Ute Kelkenberg; Andreas H. Wagner; Jasmin Sarhaddar; Markus Hecker; Heiko E. von der Leyen

From the Department of Cardiology and Angiology (U.K., J.S., H.E.v.d.L.), Hannover Medical School, Hannover, Germany, and the Department of Cardiovascular Physiology (A.H.W., M.H.), University of Goettingen, Goettingen, Germany.

Correspondence to Dr Markus Hecker, Department of Cardiovascular Physiology, University of Goettingen, Humboldtallee 23, 37073 Goettingen, Germany. E-mail hecker{at}veg-physiol.med.uni-goettingen.de

Abstract— Many cytokine genes, including those encoding acute-phase proteins and immunoglobulins, share binding sites for the CCAAT/enhancer-binding protein (C/EBP) in their 5'-flanking regions, and C/EBP-related transcription factors regulate cell proliferation during terminal differentiation. Therefore, C/EBP represents an attractive target for inhibiting restenosis after balloon angioplasty. In a rabbit model of restenosis that combines balloon injury of the carotid artery with cholesterol-mediated chronic inflammation, a decoy oligodeoxynucleotide (ODN) capable of neutralizing C/EBP was administered to the site of injury for 30 minutes. Electrophoretic mobility shift analysis confirmed that C/EBP activity in decoy ODN–treated segments was virtually absent after 2 days. Morphometric analysis after 28 days revealed significant reduction (up to 50%) of neointimal formation and intravascular inflammation in decoy ODN–treated segments compared with mutant control ODN or vehicle-treated segments. In addition, de novo synthesis of endothelin-1 and the number of proliferating cell nuclear antigen–positive smooth muscle cells in the vessel wall were markedly attenuated at day 3. These findings suggest that decoy ODN–based neutralization of C/EBP may be a feasible and effective method to limit restenosis after angioplasty brought about, at least in part, by inhibiting the de novo synthesis of endothelin-1.

Key Words: balloon injury • endothelin-1 • decoy oligodeoxynucleotides • CCAAT/enhancer-binding protein • restenosis

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