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Dominant negative c-Jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in rats

Gene Therapy volume 8, pages 1682–1689 (2001)Cite this article

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.

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, and Hoh-ansha Foundation.

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Authors and Affiliations

  1. Department of Pharmacology, Osaka City University Medical School, Osaka, Japan

    H Yasumoto, S Kim, Y Zhan & H Iwao

  2. Gene Experiment Center and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki, Japan

    H Miyazaki

  3. First Department of Internal Medicine, Osaka Medical College, Osaka, Japan

    M Hoshiga

  4. Institute for Cellular and Molecular Biology, Osaka University Medical School, Osaka, Japan

    Y Kaneda

  5. Department of Geriatric Medicine, Osaka University Medical School, Osaka, Japan

    R Morishita

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  1. H Yasumoto
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Yasumoto, H., Kim, S., Zhan, Y. et al. Dominant negative c-Jun gene transfer inhibits vascular smooth muscle cell proliferation and neointimal hyperplasia in rats. Gene Ther 8, 1682–1689 (2001). https://doi.org/10.1038/sj.gt.3301590

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