Inhibitory effect of PMC, a potent hydrophilic α-tocopherol derivative, on vascular smooth muscle cell proliferation: the pivotal role of PKC-α translocation.
BACKGROUND
Vascular smooth muscle cells (VSMCs) play a major role in the pathogenesis of atherosclerosis and restenosis, and thus the excessive proliferation of VSMCs contributes to neointimal thickening during atherosclerosis and restenosis. PMC (2,2,5,7,8-pentamethyl-6-hydroxychromane) is the most potent hydrophilic derivative of the alpha-tocopherols; it acts as a potent anti-inflammatory and free-radical scavenger.


OBJECTIVE
The present study was designed to examine the inhibitory mechanisms of PMC in VSMC proliferation.


METHODS
VSMC proliferation and cytotoxicity were measured by MTT and LDH assays, respectively. The cell cycle and translocation of PKC-alpha in VSMCs were used by flow cytometry and confocal microscope, respectively. To detect PKC-alpha translocation and activation in VSMCs, immunoblotting was performed in the present study.


RESULTS
In this study, we demonstrate an anti-proliferative effect of PMC in VSMCs. Concentration-dependent inhibition of serum-induced VSMC proliferation was observed in PMC (20 and 50 muM)-treated cells. PMC pretreatment also arrested VSMC cell cycle progression at the G2/M phase. Furthermore, PMC exhibited obvious inhibitory effects on phorbol 12-myristate 13-acetate (PMA)-induced protein kinase C (PKC)-alpha translocation and phospho-(Ser/Thr) substrate phosphorylation.


CONCLUSIONS
The inhibitory mechanisms of PMC on VSMC proliferation is mediated, at least in part, by inhibition of PKC-alpha translocation and causes cell cycle arrest in the G2/M phase. PMC treatment may represent a novel approach for lowering the risk of or improving function in abnormal VSMC proliferation-related vascular diseases.
Chang
Chao-Chien
CC
Division of Cardiology, Cathay General Hospital, Taipei.
Lee
Jie-Jen
JJ
Chiang
Cheng-Wen
CW
Jayakumar
Thanasekaran
T
Hsiao
George
G
Hsieh
Cheng-Ying
CY
Sheu
Joen-Rong
JR
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002839:Chromans / Q000302:isolation & purification / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D024502:alpha-Tocopherol / Q000302:isolation & purification / Q000494:pharmacology
D002839:Chromans; C120726:2,2,5,7,8-pentamethyl-6-hydroxychroman; D051571:Protein Kinase C-alpha; D024502:alpha-Tocopherol