title: The interleukin-1β modulator gevokizumab reduces neointimal proliferation and improves reendothelialization in a rat carotid denudation model.
abstract: OBJECTIVE
  Excessive neointima formation often occurs after arterial injury. Interleukin-1β (IL-1β) is a potent pleiotropic cytokine that has been shown to regulate neointimal proliferation. We investigated the effects of the IL-1β modulator gevokizumab in a rat carotid denudation model.
  
  
  METHODS
  Sprague-Dawley rats were subjected to balloon denudation of the right carotid artery and were then randomized to receive a single subcutaneous infusion immediately after balloon injury of saline (control group, n = 13) or gevokizumab (gevokizumab groups, n = 15 in each group: 1, 10 and 50 mg/kg). We evaluated the treatment effects on carotid intima-media thickness (IMT) using ultrasonography, on endothelial regrowth using Evans Blue staining and on inflammatory response using histology. We also assessed the effects of IL-1β and gevokizumab on human umbilical vein endothelial cells (HUVEC) and rat smooth muscle cells.
  
  
  RESULTS
  We found that carotid IMT, in the proximal part of the denuded artery at day 28, was decreased by gevokizumab 1 mg/kg compared with controls. Neointima area and the intima/media area ratio were both reduced in the gevokizumab 1 mg/kg-treated group. Gevokizumab at the 1 mg/kg dose also improved endothelial regrowth. No effect was observed with gevokizumab 10 or 50 mg/kg. Gevokizumab also decreased the inflammatory effect of IL-1β in in vitro cell experiments and protected HUVECs from IL-1β's deleterious effects on cell migration, apoptosis and proliferation.
  
  
  CONCLUSIONS
  A single administration of gevokizumab 1 mg/kg improves endothelial regrowth and reduces neointima formation in rats following carotid denudation, at least in part through its beneficial effects on endothelial cells.
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Roubille
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Busseuil
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Walid
authors.initials: W
authors.lastname: Nachar
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Téodora
authors.initials: T
authors.lastname: Mihalache-Avram
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Mecteau
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Gillis
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Brand
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Théberge-Julien
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Mathieu R
authors.initials: MR
authors.lastname: Brodeur
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Anne-Elen
authors.initials: AE
authors.lastname: Kernaleguen
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada.
authors.forename: Mélania
authors.initials: M
authors.lastname: Gombos
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Rhéaume
authors.affiliation: Research Centre, Montreal Heart Institute, Montreal, Quebec, Canada; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada. Electronic address: jean-claude.tardif@icm-mhi.org.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Tardif
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001011:Aorta / Q000166:cytology; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D017536:Carotid Artery, Common / Q000000981:diagnostic imaging / Q000473:pathology; D059168:Carotid Intima-Media Thickness; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D004730:Endothelium, Vascular / Q000503:physiopathology; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology / Q000502:physiology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D058426:Neointima / Q000188:drug therapy / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration; D014657:Vasculitis / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053583:Interleukin-1beta; C547697:gevokizumab
keywords: Carotid artery denudation; Endothelium; Gevokizumab; Interleukin-1β; Neointima formation