title: Divergent roles of NF-κB and Egr-1 in flow-dependent restenosis after angioplasty and stenting.
abstract: OBJECTIVE
  Restenosis after both angioplasty and stenting is flow dependent. The effects of flow are preventable with the antioxidant pyrrolidine dithiocarbamate (PDTC) after angioplasty but not after stenting. We examined to what extent these observations could be explained by the effect of PDTC on NF-κB and Egr-1, two transcription factors which are both flow- and redox-sensitive.
  
  
  METHODS
  In a flow-modified rabbit carotid model of angioplasty and stenting, we assessed the effects of altered flow, injury and PDTC on expression of Egr-1 and nuclear binding activity of NF-κB. We also examined the effects of local delivery of decoy oligodeoxynucleotides (ODN) specific for NF-κB and Egr-1 on morphology at 28 days in normal and low flow.
  
  
  RESULTS
  The activity of both transcription factors was enhanced by injury (stent>balloon alone) and was further augmented by low flow. PDTC markedly attenuated the activity of NF-κB but not Egr-1. Specific decoy ODN for Egr-1 attenuated intima formation in both stented and balloon injured vessels in both normal and low flow but had no effect on remodelling. In contrast while NF-κB decoy ODN caused a modest but significant reduction in intima formation, there was a striking effect on remodelling in low flow vessels only.
  
  
  CONCLUSIONS
  We conclude that Egr-1 plays a pivotal role in intima formation under all flow conditions and that NF-κB plays a key role in flow-sensitive remodelling after angioplasty and that NF-κB inhibition likely accounts for a significant part of the morphological effects of PDTC after vessel injury.
authors.affiliation: Department of Cardiology, Royal North Shore Hospital and University of Sydney, St Leonards, NSW 2065, Australia.
authors.forename: Melanie
authors.initials: M
authors.lastname: Murrell
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.forename: Michael R
authors.initials: MR
authors.lastname: Ward
mesh_terms: D017130:Angioplasty / Q000379:methods; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D023903:Coronary Restenosis / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D008081:Liposomes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D010084:Oxidation-Reduction; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D015607:Stents; D013859:Thiocarbamates / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000975:Antioxidants; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D008081:Liposomes; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D009841:Oligonucleotides; D011759:Pyrrolidines; D013859:Thiocarbamates; D014157:Transcription Factors; C020972:pyrrolidine dithiocarbamic acid