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Dominant negative c-jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia
1Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
Abstract:
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.
Insights
This study shows that inhibiting c-Jun, a component of activator protein-1 (AP-1), prevents vascular smooth muscle cell proliferation. This finding suggests AP-1 is a potential therapeutic target for vascular diseases.
Area of Science:
- Vascular Biology
- Molecular Biology
- Cellular Biology
Background:
- Vascular smooth muscle cell (SMC) proliferation contributes to intimal hyperplasia after arterial injury.
- Activator protein-1 (AP-1), including c-Jun, is rapidly activated in balloon-injured arteries.
Purpose of the Study:
- To investigate the role of c-Jun in vascular SMC proliferation.
- To evaluate the therapeutic potential of inhibiting c-Jun in vascular diseases.
Main Methods:
- Utilized in vitro and in vivo gene transfer techniques.
- Employed recombinant adenovirus carrying dominant-negative c-Jun (Ad-DN-c-Jun) to inhibit AP-1.
- Assessed SMC proliferation via 3H-thymidine incorporation and cell counts.
- Examined the effect of DN-c-Jun on balloon injury-induced intimal hyperplasia in rat carotid arteries.
Main Results:
- Serum stimulation increased AP-1 DNA binding activity and SMC proliferation in vitro.
- Ad-DN-c-Jun inhibited serum-induced SMC proliferation by blocking S phase entry.
- In vivo transfection of DN-c-Jun into rat carotid arteries significantly reduced SMC proliferation and intimal thickening post-balloon injury.
Conclusions:
- c-Jun plays a critical role in vascular SMC proliferation.
- Inhibition of c-Jun via gene transfer effectively prevents vascular SMC proliferation both in vitro and in vivo.
- AP-1, specifically c-Jun, represents a promising therapeutic target for intimal hyperplasia and related vascular diseases.
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