Effects of dominant-negative c-Jun on platelet-derived growth factor-induced vascular smooth muscle cell proliferation

被引:31
作者
Zhan, YM
Kim, S
Yasumoto, H
Namba, M
Miyazaki, H
Iwao, H
机构
[1] Osaka City Univ, Sch Med, Dept Pharmacol, Abeno Ku, Osaka 5458585, Japan
[2] Univ Tsukuba, Gene Expt Ctr, Tsukuba, Ibaraki 305, Japan
[3] Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 305, Japan
关键词
platelet-derived growth factor; smooth muscle cells; c-Jun; gene transfer; proliferation;
D O I
10.1161/hq0102.101821
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Although platelet-derived growth factor (PDGF)-BB is thought to participate in vascular disorders, the mechanism of PDGF-induced vascular smooth muscle cell (SMC) proliferation is not fully understood. This study was undertaken to examine the role of c-Jun in PDGF-BB-induced proliferation of rat aortic SMCs. PDGF-BB (10 ng/mL) significantly increased activator protein (AP)-1 DNA binding activity in SMCs, followed by the increase in [H-3]thymidine incorporation and cell number. SMCs were infected with recombinant adenovirus containing TAM67, a dominant-negative c-Jun lacking the transactivation domain of wild c-Jun (Ad-DN-c-Jun), to inhibit endogenous AP-1. Ad-DN-c-Jun, which specifically blocked AP-1 transcriptional activity, significantly inhibited PDGF-BB-induced increases in [H-3]thymidine incorporation or cell number. As shown by flow cytometric analysis, Ad-DN-c-Jun inhibited PDGF-BB-induced entrance of SMCs into S phase, leading to a G(1) arrest. Ad-DN-c-Jun attenuated PDGF-BB-induced downregulation of p27(Kip1), as shown by Western blot analysis, and the prevented PDGF-BB-induced decrease in cyclin E/cyclin-dependent kinase 2 complex-associated p27(Kip1), as shown by immunoprecipitation study. Furthermore, protein kinase assay showed that Ad-DN-c-Jun blocked PDGF-BB-induced activation of cyclin-dependent kinase 2. Our results provide the first evidence that dominant-negative c-Jun inhibits PDGF-BB-induced vascular SMC proliferation by preventing the downreguiation of p27(Kip1), thereby supporting the important role of c-Jun in vascular SMC proliferation.
引用
收藏
页码:82 / 88
页数:7
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