title: Trichostatin A prevents neointimal hyperplasia via activation of Krüppel like factor 4.
abstract: 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 Krüppel like factor 4 (KLF4) blocked the cell proliferation and DNA synthesis, as determined by the MTT and [³H]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.
authors.affiliation: Department of Pharmacology and Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea. sshjkee@empas.com
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.forename: Jin-Sook
authors.initials: JS
authors.lastname: Kwon
authors.forename: Sera
authors.initials: S
authors.lastname: Shin
authors.forename: Youngkeun
authors.initials: Y
authors.lastname: Ahn
authors.forename: Myung Ho
authors.initials: MH
authors.lastname: Jeong
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020868:Gene Silencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006965:Hyperplasia; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D011994:Recombinant Proteins; C012589:trichostatin A