期刊
VASCULAR PHARMACOLOGY
卷 55, 期 5-6, 页码 127-134出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2011.07.001
关键词
Trichostatin A; Kruppel like factor 4; Neointimal hyperplasia; Vascular smooth muscle cell; Cell cycle regulator
资金
- Korea Healthcare Technology RD Project
- Ministry for Health, Welfare & Family Affairs, Republic of Korea [A090430, A084869]
- Ministry of Education, Science and Technology [2009-0064200]
- Korea Health Promotion Institute [A090430] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2009-0064200] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The proliferation of vascular smooth muscle cells (VSMCs) is an integral part of the mechanism of vascular diseases such as restenosis. Post-translational modifications by histone deacetylase (HDAC) inhibitors play an important role in the regulation of gene expression by inducing cell cycle arrest. However, the role and mechanism of the HDAC inhibitor trichostatin A (TSA) on neointimal proliferation remain unknown. In this study, we investigated the effect and mechanism whereby TSA prevents the proliferation of VSMCs and neointimal hyperplasia induced by balloon injury in rat carotid artery. Local administration of TSA significantly prevented neointimal hyperplasia. TSA dramatically inhibited the proliferation and DNA synthesis of VSMCs in response to FBS or PDGF-BB. Overexpression of Kruppel like factor 4 (KLF4) blocked the cell proliferation and DNA synthesis, as determined by the MTT and [H-3]thymidine incorporation assays, whereas knockdown of KLF4 resulted in an increase in VSMC proliferation. In VSMCs, TSA increased the mRNA level and protein expression of KLF4. Treatment with TSA or transfection of KLF4 increased the expression of both p21 and p27 and promoter activity. In addition, the anti-proliferative activity of TSA was recovered in KLF4-knockdown cells. These data demonstrate that TSA inhibits neointimal thickening and VSMC proliferation via activation of the KLF4/p21/p27 signaling pathway. (C) 2011 Elsevier Inc. All rights reserved.
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