title: Catalytic antisense DNA molecules targeting Egr-1 inhibit neointima formation following permanent ligation of rat common carotid arteries.
abstract: Animal models of neointima (NI) formation have proven useful in gaining insights into the mechanisms of restenosis after coronary angioplasty and stenting, but the events at a molecular level remain incompletely understood. Here, we describe a technically straightforward, rat model of NI formation, involving complete ligation of the common carotid artery and demonstrate the importance of the immediate-early gene and zinc finger transcription factor Egr-1 in this process. Acute cessation of common carotid blood flow by vessel ligation, was followed by the expression of Egr-1 in the arterial media within 3 h and NI formation proximal to the point of ligation at 18 days. Local delivery of catalytic oligodeoxynucleotides (ODN) targeting rat Egr-1 mRNA at the time of ligation reduced both Egr-1 expression and NI formation in this model. In contrast, a scrambled version of this ODN had no inhibitory effect. These studies demonstrate for the first time that arterial intimal thickening following artery ligation is critically-dependent on the activation of Egr-1.
authors.affiliation: Centre for Thrombosis and Vascular Research, School of Pathology, The University of New South Wales and Department of Haematology, The Prince of Wales Hospital, Sydney, Australia.
authors.forename: Harry C
authors.initials: HC
authors.lastname: Lowe
authors.forename: Colin N
authors.initials: CN
authors.lastname: Chesterman
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D016893:Carotid Stenosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016373:DNA, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D021881:DNA, Catalytic / Q000008:administration & dosage / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051766:Early Growth Response Protein 1; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early / Q000187:drug effects; D017874:Immediate-Early Proteins; D007269:Injections, Intra-Arterial; D008026:Ligation; D008297:Male; D023421:Models, Animal; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D017539:Tunica Intima / Q000473:pathology*
chemical_list: D016373:DNA, Antisense; D021881:DNA, Catalytic; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D014157:Transcription Factors