CCAAT/enhancer-binding protein decoy oligodeoxynucleotide inhibition of macrophage-rich vascular lesion formation in hypercholesterolemic rabbits.
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.
Kelkenberg
Ute
U
Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
Wagner
Andreas H
AH
Sarhaddar
Jasmin
J
Hecker
Markus
M
von der Leyen
Heiko E
HE
D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology / Q000628:therapy; D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors*; D002404:Catheterization / Q000009:adverse effects; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis; D006937:Hypercholesterolemia / Q000503:physiopathology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000473:pathology*; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000378:metabolism / Q000627:therapeutic use*; D011817:Rabbits; D012008:Recurrence; D016896:Treatment Outcome; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology
D022762:CCAAT-Enhancer-Binding Proteins; D019332:Endothelin-1; D009838:Oligodeoxyribonucleotides