Dominant negative c-jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in rats.
We previously reported that activator protein-1 (AP-1), containing c-Jun, is rapidly activated in balloon-injured artery. Therefore, we examined the role of c-Jun in vascular smooth muscle cell (SMC) proliferation, by using in vitro and in vivo gene transfer techniques. (1) Serum (2%) stimulation significantly increased AP-1 DNA binding activity in aortic SMCs, followed by the increase in both 3H-thymidine incorporation and cell number. Aortic SMCs were infected with recombinant adenovirus containing TAM67, a dominant negative c-Jun lacking transactivation domain of wild c-Jun (Ad-DN-c-Jun), to specifically inhibit AP-1. Ad-DN-c-Jun significantly inhibited serum-induced SMC proliferation, by inhibiting the entrance of SMC into S phase. (2) The effect of DN-c-Jun was examined on balloon injury-induced intimal hyperplasia in rats. Before balloon injury, DN-c-Jun was transfected into rat carotid artery using the hemagglutinating virus of Japan-liposome method. In vivo transfection of DN-c-Jun significantly inhibited vascular SMC proliferation in the intima and the media and subsequently prevented intimal thickening at 14 days after balloon injury. We obtained the first evidence that DN-c-Jun gene transfer prevented vascular SMC proliferation in vitro and in vivo, and c-Jun was involved in balloon injury-induced intimal hyperplasia. Thus, AP-1 seems to be the new therapeutic target for treatment of vascular diseases.
Yasumoto
H
H
Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
Kim
S
S
Zhan
Y
Y
Miyazaki
H
H
Hoshiga
M
M
Kaneda
Y
Y
Morishita
R
R
Iwao
H
H
D000818:Animals; D001011:Aorta; D020212:Carotid Artery Injuries / Q000473:pathology / Q000628:therapy; D002455:Cell Division / Q000235:genetics; D015870:Gene Expression; D016758:Genes, jun; D015316:Genetic Therapy / Q000379:methods*; D006965:Hyperplasia / Q000235:genetics; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
D018808:Transcription Factor AP-1