Inhibition of vascular smooth muscle cell proliferation by the vitamin E derivative pentamethylhydroxychromane in an in vitro and in vivo study: pivotal role of hydroxyl radical-mediated PLCgamma1 and JAK2 phosphorylation.
Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development of cardiovascular diseases. PMC (2,2,5,7,8-pentamethyl-6-hydroxychromane) is the most potent hydrophilic derivative of vitamin E. In this study, we investigated the mechanisms of PMC inhibition of VSMC proliferation in vitro and in vivo. PMC (20 and 50 microM) obviously suppressed proliferation of PDGF-BB-stimulated cells, but not resting cells, and arrested cell cycle progression at the G(2)/M phase. A significant reduction in neointimal formation in carotid arteries was observed in PMC (5mg/kg/day)-treated rats after balloon angioplasty. Activation of STAT3, JAK2, PLCgamma1, PKCdelta, and ROS, but not ERK1/2, AKT, or PKCalpha, was markedly inhibited by PMC in PDGF-BB-stimulated VSMCs. Deferoxamine and PMC significantly inhibited the phosphorylation of PLCgamma1 and JAK2 and arrested cell cycle progression at the G(2)/M phase. These events, however, were reversed in the presence of Fe(2+). Moreover, PMC directly inhibited hydroxyl radical formation in both the Fenton reaction and VSMCs according to an electron spin resonance study. In conclusion, this study demonstrates for the first time that PMC inhibits VSMC proliferation in vitro and balloon injury-induced neointimal formation in vivo. The inhibitory mechanism of PMC may involved the inhibition of hydroxyl radical-mediated PLCgamma1-PKCdelta and JAK2-STAT3 activation and causes cell cycle arrest at the G(2)/M phase. PMC treatment may represent a novel approach for lowering the risk of or improving function in abnormal VSMC proliferation-related vascular diseases.
Hsieh
Cheng-Ying
CY
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan.
Liu
Chien-Liang
CL
Hsu
Ming-Jen
MJ
Jayakumar
Thanasekaran
T
Chou
Duen-Suey
DS
Wang
Yi-Hsuan
YH
Hsiao
George
G
Sheu
Joen-Rong
JR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D017665:Hydroxyl Radical / Q000494:pharmacology*; D053614:Janus Kinase 2 / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051966:Phospholipase C gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives / Q000494:pharmacology
C554178:2,2,5,7,8-pentamethyl-6-hydroxychromane; D000975:Antioxidants; D001578:Benzopyrans; D017382:Reactive Oxygen Species; D014810:Vitamin E; D017665:Hydroxyl Radical; D053614:Janus Kinase 2; D051966:Phospholipase C gamma