Inhibitory effects of novel AP-1 decoy oligodeoxynucleotides on vascular smooth muscle cell proliferation in vitro and neointimal formation in vivo.
Excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal formation are critical steps in the pathogenesis of atherosclerosis and restenosis after percutaneous transluminal angioplasty. In this study, we investigated the hypothesis that the activator protein-1 (AP-1) plays an important role in neointimal formation after vascular injury. A circular dumbbell AP-1 decoy oligodeoxynucleotide (CDODN) was developed as a novel therapeutic strategy for restenosis after angioplasty. This CDODN was more stable than the conventional phosphorothioate linear decoy ODN (PSODN) and maintained structural integrity on exposure to exonuclease III or serum. Transfection with AP-1 decoy ODNs strongly inhibited VSMC proliferation and migration, as well as glucose- and serum-induced expression of PCNA and cyclin A genes. Administration of AP-1 decoy ODNs in vivo using the hemagglutinating virus of Japan (HVJ)-liposome method virtually abolished neointimal formation after balloon injury to the rat carotid artery. Compared with PSODN, CDODN was more effective in inhibiting the proliferation of VSMCs in vitro and neointimal formation in vivo. Our results collectively indicate that AP-1 activation is crucial for the mediation of VSMC proliferation in response to vascular injury. Moreover, the use of stable CDODN specific for AP-1 activity in combination with the highly effective HVJ-liposome method provides a novel potential therapeutic strategy for the prevention of restenosis after angioplasty in humans.
Ahn
Jong Deok
JD
Department of Microbiology, Kyungpook National University, Taegu, Korea.
Morishita
Ryuichi
R
Kaneda
Yasufumi
Y
Lee
Sang-Jun
SJ
Kwon
Ki-Young
KY
Choi
Se-Young
SY
Lee
Ki-Up
KU
Park
Joong-Yeol
JY
Moon
Ik-Jae
IJ
Park
Jong-Gu
JG
Yoshizumi
Masao
M
Ouchi
Yasuyoshi
Y
Lee
In-Kyu
IK
D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D016893:Carotid Stenosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004270:DNA, Circular / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects
D004270:DNA, Circular; D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D018808:Transcription Factor AP-1