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

doi:10.1016/j.freeradbiomed.2010.06.014

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Title:	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
Authors:	Hsieh, C.-Y.;Liu, C.-L.;Wang, Yi Hsuan
Contributors:	法科所
Keywords:	6 hydroxy 2,2,5,7,8 pentamethylchroman;alpha tocopherol;deferoxamine;ferrous ion;hydroxyl radical;Janus kinase 2;mitogen activated protein kinase 1;mitogen activated protein kinase 3;phospholipase C gamma1;protein kinase B;protein kinase C alpha;protein kinase C delta;reactive oxygen metabolite;recombinant platelet derived growth factor BB;STAT3 protein;animal cell;animal experiment;artery intima proliferation;article;carotid artery injury;cell cycle arrest;cell cycle G0 phase;cell cycle G1 phase;cell cycle G2 phase;cell cycle M phase;cell cycle progression;cell stimulation;common carotid artery;controlled study;dose response;drug effect;drug mechanism;electron spin resonance;enzyme inhibition;enzyme phosphorylation;Fenton reaction;in vitro study;in vivo study;male;nonhuman;percutaneous transluminal angioplasty;priority journal;rat;smooth muscle fiber;vascular smooth muscle;Animals;Antioxidants;Benzopyrans;Cell Cycle;Cell Proliferation;Cells, Cultured;Down-Regulation;Drug Evaluation, Preclinical;Hydroxyl Radical;Janus Kinase 2;Male;Muscle, Smooth, Vascular;Myocytes, Smooth Muscle;Phospholipase C gamma;Phosphorylation;Rats;Rats, Wistar;Reactive Oxygen Species;Vitamin E;Rattus
Date:	2010-09
Issue Date:	2015-06-10 15:05:52 (UTC+8)
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. © 2010 Elsevier Inc.
Relation:	Free Radical Biology and Medicine, Volume 49, Issue 5, Pages 881-893
Data Type:	article
DOI 連結:	http://dx.doi.org/http://dx.doi.org/10.1016/j.freeradbiomed.2010.06.014
DOI:	10.1016/j.freeradbiomed.2010.06.014
Appears in Collections:	[法律科際整合研究所] 期刊論文

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