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

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 mu M) 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 (5 mg/kg/day)-treated rats after balloon angioplasty Activation of STAT3. JAK2. PLC gamma 1, PKC delta, and ROS. but not ERK1/2, AKT, or PKC alpha, was markedly inhibited by PMC in PDGF-BB-stimulated VSMCs Deferoxamine and PMC significantly inhibited the phosphorylation of PLC gamma 1 and JAK2 and arrested cell cycle progression at the G(2)/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 election 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 PLC gamma 1-PKC delta 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 (C) 2010 Elsevier Inc All rights reserved.