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

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 aor...

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Veröffentlicht in:Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2002-01, Vol.22 (1), p.82-88
Hauptverfasser: Zhan, Yumei, Kim, Shokei, Yasumoto, Hideo, Namba, Masashi, Miyazaki, Hitoshi, Iwao, Hiroshi
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Sprache:eng
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Zusammenfassung: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]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]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, as shown by Western blot analysis, and the prevented PDGF-BB-induced decrease in cyclin E/cyclin-dependent kinase 2 complex-associated p27, 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, thereby supporting the important role of c-Jun in vascular SMC proliferation.
ISSN:1079-5642
1524-4636
DOI:10.1161/hq0102.101821