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.

Mediation of the single-walled carbon nanotubes induced pulmonary fibrogenic response by osteopontin and TGF-β1

“…One should also consider the other important mechanisms and cytokine interactions involved in the pulmonary fibrosis induction and progression, such as combined action of PDGF and TGF- β 1. [61] PDGF itself, which was found to be upregulated in SWCNT-treated animals, [26] also participates in upregulating the expression of OPN [86,87] and may implement its action in part through the OPN promotion, which has been shown for the smooth muscle cells. [88,89] There’s little data as of yet regarding the possible OPN upstream effects on PDGF signaling, but interestingly, one of the recent papers describes the hampering of Focal adhesion kinase (FAK) phosphorylation by PDGF in osteoblasts and fibroblasts upon the recombinant OPN treatment, [90] thus potentially reducing their migration activity.…”

Identification of Volatile Compounds (VCs) in the Leaves Collected from ‘Gemlik’, ‘Halhalı’ and ‘Sarı Hasebi’ Olive Tree Varieties

“…α-Cubebene identified in 'Halhalı' olive leaf as the major VC is a dibenzocyclooctadiene lignin and it has a potential antioxidant property [12]. It has previously been identified in Schisandra chinensis herb as the most plentiful VC [13]. This plant is a well-known medicinal herb that ameliorates cardiovascular symptoms.…”

α-Isocubebene modulates vascular tone by inhibiting myosin light chain phosphorylation in murine thoracic aorta

“…Also, ICB has neuroprotective [ 25 27 28 ] and anti-inflammatory effects, the latter of which was attributed to the inhibition of endothelial expression of adhesion molecules [ 26 ]. In our previous study, ICB has been suggested to be therapeutically useful in proliferative vascular diseases by inhibiting VSMC proliferation [ 29 ]. Although ICB has been suggested to have beneficial effects on various cardiovascular symptoms, the mechanisms underlying its potential protective effects have not yet been fully investigated.…”