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 PLCγ1 and JAK2 phosphorylation

Cheng Ying Hsieh, Chien Liang Liu, Ming Jen Hsu, Thanasekaran Jayakumar, Duen Suey Chou, Yi Hsuan Wang, George Hsiao, Joen Rong Sheu

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10 Citations (Scopus)

Abstract

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 50γM) obviously suppressed proliferation of PDGF-BB-stimulated cells, but not resting cells, and arrested cell cycle progression at the G2/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, PLCγ1, PKCγ, and ROS, but not ERK1/2, AKT, or PKCγ, was markedly inhibited by PMC in PDGF-BB-stimulated VSMCs. Deferoxamine and PMC significantly inhibited the phosphorylation of PLCγ1 and JAK2 and arrested cell cycle progression at the G2/M phase. These events, however, were reversed in the presence of Fe2+. 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 PLCγ1-PKCγ and JAK2-STAT3 activation and causes cell cycle arrest at 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.

Original languageEnglish
Pages (from-to)881-893
Number of pages13
JournalFree Radical Biology and Medicine
Volume49
Issue number5
DOIs
Publication statusPublished - Sep 2010

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Keywords

  • Free radicals
  • Hydroxyl radical
  • JAK2
  • PLCγ1
  • PMC
  • Vitamin E derivative
  • VSMC

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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