title: A novel agent with histone deacetylase inhibitory activity attenuates neointimal hyperplasia.
abstract: OBJECTIVE
  Neointimal hyperplasia (NIH), a pathophysiological event identified in bypass graft and stent re-stenosis, is characterised by aberrant vascular smooth muscle cell (VSMC) migration and proliferation. Recent evidence identifies histone deacetylase modulation as a regulator of VSMC proliferation and migration and a potential therapeutic target in the treatment of NIH. The purpose of our study was to determine the in vitro and in vivo potential of a novel agent, MCT-3, to modulate VSMC migration, proliferation and NIH.
  
  
  METHODS
  In vitro VSMC studies utilized reverse transcriptase and real time Q-PCR gene expression analysis, western blot, elisa assay and cellular proliferation and migration scratch assay's. In vivo studies utilized the partial carotid artery ligation model of NIH together with immunohistochemistry in FVB/N mice.
  
  
  RESULTS
  MCT-3 treatment induced histone H3 and H4 acetylation and inhibited VSMC migration and proliferation in vitro and significantly attenuated NIH in vivo. MCT-3-mediated regulation of orphan nuclear receptor NUR77, Plasminogen Activator Inhibitor Type-1 (PAI-1) and cyclin dependent kinase inhibitors (CDKI) p21(CIP1/WAF1) and p27(KIP1) expression was also identified.
  
  
  CONCLUSIONS
  Together these observations identify a novel agent, MCT-3, with histone deacetylase inhibitory activity, able to inhibit NIH and identify a potential molecular mechanism responsible for these effects. Additional pre-clinical studies may be warranted to determine the potential clinical utility of this compound.
authors.affiliation: Australian Centre for Blood Diseases, Department of Medicine, Translational Research Division, Eastern Clinical Research Unit, AMREP Facility, Monash University, 6th Floor Burnet Tower, 89 Commercial Rd, Prahran 3181, Melbourne, VIC, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Rahmatzadeh
authors.forename: H B
authors.initials: HB
authors.lastname: Liu
authors.forename: S M
authors.initials: SM
authors.lastname: Krishna
authors.forename: T A
authors.initials: TA
authors.lastname: Gaspari
authors.forename: I
authors.initials: I
authors.lastname: Welungoda
authors.forename: R E
authors.initials: RE
authors.lastname: Widdop
authors.forename: A E
authors.initials: AE
authors.lastname: Dear
mesh_terms: D000107:Acetylation; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D006965:Hyperplasia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy* / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D051381:Rats
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D017395:Plasminogen Activator Inhibitor 1; D050760:Cyclin-Dependent Kinase Inhibitor p27