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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:82.)
© 2002 American Heart Association, Inc.

Vascular Biology

Effects of Dominant-Negative c-Jun on Platelet-Derived Growth Factor–Induced Vascular Smooth Muscle Cell Proliferation

Yumei Zhan; Shokei Kim; Hideo Yasumoto; Masashi Namba; Hitoshi Miyazaki; Hiroshi Iwao

From the Department of Pharmacology, Osaka City University Medical School, Osaka, Japan, and the Gene Experiment Center and Center for Tsukuba Advanced Research Alliance (H.M.), University of Tsukuba, Ibaraki, Japan.

Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp

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 [³H]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 [³H]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 G₁ 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 downregulation of p27^Kip1, thereby supporting the important role of c-Jun in vascular SMC proliferation.

Key Words: platelet-derived growth factor • smooth muscle cells • c-Jun • gene transfer • proliferation

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