title: α-Iso-Cubebene Inhibits PDGF-Induced Vascular Smooth Muscle Cell Proliferation by Suppressing Osteopontin Expression.
abstract: α-Iso-cubebene (ICB) is a dibenzocyclooctadiene lignin contained in Schisandra chinensis (SC), a well-known medicinal herb that ameliorates cardiovascular symptoms. Thus, we examined the effect of ICB on vascular smooth muscle cell (VSMC) proliferation, a key feature of diverse vascular diseases. When VSMCs primary cultured from rat thoracic aorta were stimulated with PDGF (1-10 ng/ml), cell proliferation and osteopontin (OPN) expression were concomitantly up-regulated, but these effects were attenuated when cells were treated with MPIIIB10, a neutralizing monoclonal antibody for OPN. In aortic tissues exposed to PDGF, sprouting VSMC numbers increased, which was attenuated in tissues from OPN-deficient mice. Furthermore, VSMC proliferation and OPN expression induced by PDGF were attenuated dose-dependently by ICB (10 or 30 μg/ml). Reporter assays conducted using OPN promoter-luciferase constructs showed that the promoter region 538-234 bp of the transcription start site was responsible for transcriptional activity enhancement by PDGF, which was significantly inhibited by ICB. Putative binding sites for AP-1 and C/EBPβ in the indicated promoter region were suggested by TF Search, and increased binding of AP-1 and C/EBPβ in PDGF-treated VSMCs was demonstrated using a ChIP assay. The increased bindings of AP-1 and C/EBPβ into OPN promoter were attenuated by ICB. Moreover, the PDGF-induced expression of OPN was markedly attenuated in VSMCs transfected with siRNA for AP-1 and C/EBPβ. These results indicate that ICB inhibit VSMC proliferation by inhibiting the AP-1 and C/EBPβ signaling pathways and thus downregulating OPN expression.
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam, Republic of Korea.|Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam, Republic of Korea.
authors.forename: Min A
authors.initials: MA
authors.lastname: Jang
authors.affiliation: College of Pharmacy, Pusan National University, Busan, Republic of Korea.
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam, Republic of Korea.|Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam, Republic of Korea.
authors.forename: Seung Eun
authors.initials: SE
authors.lastname: Baek
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam, Republic of Korea.|Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam, Republic of Korea.
authors.forename: So Youn
authors.initials: SY
authors.lastname: Park
authors.affiliation: College of Natural Resources & Life Sciences, Pusan National University, Gyeongnam, Republic of Korea.
authors.forename: Young Whan
authors.initials: YW
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, School of Medicine, Pusan National University, Gyeongnam, Republic of Korea.|Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Gyeongnam, Republic of Korea.
authors.forename: Chi Dae
authors.initials: CD
authors.lastname: Kim
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053495:Osteopontin / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D010982:Platelet-Derived Growth Factor; D012717:Sesquiterpenes; C539088:alpha-iso-cubebene; D053495:Osteopontin