title: Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition.
abstract: OBJECTIVE
  Proliferation of smooth muscle cells (SMC) in response to vascular injury is central to neointimal vascular remodeling. There is accumulating evidence that histone acetylation constitutes a major epigenetic modification for the transcriptional control of proliferative gene expression; however, the physiological role of histone acetylation for proliferative vascular disease remains elusive.
  
  
  RESULTS
  In the present study, we investigated the role of histone deacetylase (HDAC) inhibition in SMC proliferation and neointimal remodeling. We demonstrate that mitogens induce transcription of HDAC 1, 2, and 3 in SMC. Short interfering RNA-mediated knockdown of either HDAC 1, 2, or 3 and pharmacological inhibition of HDAC prevented mitogen-induced SMC proliferation. The mechanisms underlying this reduction of SMC proliferation by HDAC inhibition involve a growth arrest in the G(1) phase of the cell cycle that is due to an inhibition of retinoblastoma protein phosphorylation. HDAC inhibition resulted in a transcriptional and posttranscriptional regulation of the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip). Furthermore, HDAC inhibition repressed mitogen-induced cyclin D1 mRNA expression and cyclin D1 promoter activity. As a result of this differential cell cycle-regulatory gene expression by HDAC inhibition, the retinoblastoma protein retains a transcriptional repression of its downstream target genes required for S phase entry. Finally, we provide evidence that these observations are applicable in vivo by demonstrating that HDAC inhibition decreased neointima formation and expression of cyclin D1 in a murine model of vascular injury.
  
  
  CONCLUSIONS
  These findings identify HDAC as a critical component of a transcriptional cascade regulating SMC proliferation and suggest that HDAC might play a pivotal role in the development of proliferative vascular diseases, including atherosclerosis and in-stent restenosis.
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Hannes M
authors.initials: HM
authors.lastname: Findeisen
authors.forename: Florence
authors.initials: F
authors.lastname: Gizard
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hua
authors.initials: H
authors.lastname: Qing
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Heywood
authors.forename: Karrie L
authors.initials: KL
authors.lastname: Jones
authors.forename: Dianne
authors.initials: D
authors.lastname: Cohn
authors.forename: Dennis
authors.initials: D
authors.lastname: Bruemmer
mesh_terms: D000107:Acetylation; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D050684:E2F Transcription Factors / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006898:Hydroxylamines / Q000494:pharmacology*; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D051381:Rats; D016160:Retinoblastoma Protein / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D017540:Tunica Media / Q000187:drug effects* / Q000201:enzymology / Q000293:injuries / Q000473:pathology; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
chemical_list: C530105:Ccnd1 protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050684:E2F Transcription Factors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006898:Hydroxylamines; D011804:Quinolines; D016160:Retinoblastoma Protein; C410733:scriptaid; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006655:Histone Deacetylases