Abstract
In the present study, we have investigated the bee venom (BV) and melittin (a major component of BV)-mediated antiproliferative effect and defined its mechanisms of action in cultured rat aortic vascular smooth muscle cell(s) (VSMC). BV and melittin (∼0.4–0.8 μg/ml) effectively inhibited 5% fetal bovine serum-induced and 50 ng/ml platelet-derived growth factor BB (PDGF-BB)-induced VSMC proliferation. The regulation of apoptosis has attracted much attention as a possible means of eliminating excessively proliferating VSMC. In the present study, the treatment of BV and melittin strongly induced apoptosis of VSMC. To investigate the antiproliferative mechanism of BV and melittin, we examined the effect of melittin on nuclear factor κB (NF-κB) activation, the PDGF-BB-induced IκBα phosphorylation, and its degradation were potently inhibited by melittin and whether DNA binding activity and nuclear translocation of NF-κB p50 subunit in response to the action of PDGF-BB were potently attenuated by melittin. In further investigations, melittin markedly inhibited the PDGF-BB-induced phosphorylation of Akt and weakly inhibited phosphorylation of extracellular signal-regulated kinase 1/2, upstream signals of NF-κB. Treatment of melittin also potently induced proapoptotic protein p53, Bax, and caspase-3 expression but decreased antiapoptotic protein Bcl-2 expression. These results suggest the antiproliferative effects of BV and melittin in VSMC through induction of apoptosis via suppressions of NF-κB and Akt activation and enhancement of apoptotic signaling pathway.
Footnotes
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This work was supported by a Chungbuk National University grant in 2005.
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doi:10.1124/jpet.105.095901.
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ABBREVIATIONS: VSMC, vascular smooth muscle cell(s); BV, bee venom; PDGF, platelet-derived growth factor; FBS, fetal bovine serum; NF-κB, nuclear factor κB; ERK1/2, extracellular signal-regulated kinase; Bcl-2, B-cell leukemia/lymphoma-2; DMEM, Dulbecco's modified Eagle's medium; Bax, Bcl-2-associated X protein; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; DAPI, 4,6-diamidino-2-phenylindole; EMSA, electrophoretic mobility shift assay; Z-DEVD-FMK, N-benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethyl ketone; FITC, fluorescein isothiocyanate; MAPK, mitogen-activated protein kinase.
- Received September 20, 2005.
- Accepted January 5, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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