Melittin inhibits vascular smooth muscle cell proliferation through induction of apoptosis via suppression of nuclear factor-kappaB and Akt activation and enhancement of apoptotic protein expression.
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 ( approximately 0.4-0.8 microg/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 kappaB (NF-kappaB) activation, the PDGF-BB-induced IkappaBalpha phosphorylation, and its degradation were potently inhibited by melittin and whether DNA binding activity and nuclear translocation of NF-kappaB 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-kappaB. 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-kappaB and Akt activation and enhancement of apoptotic signaling pathway.
Son
Dong Ju
DJ
College of Pharmacy, Chungbuk National University, Cheongju 361-763, Chungbuk, Korea.
Ha
Seong Jong
SJ
Song
Ho Sueb
HS
Lim
Yong
Y
Yun
Yeo Pyo
YP
Lee
Jae Woong
JW
Moon
Dong Cheul
DC
Park
Young Hyun
YH
Park
Byeoung Soo
BS
Song
Min Jong
MJ
Hong
Jin Tae
JT
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008555:Melitten / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D008555:Melitten; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases