title: The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice.
abstract: OBJECTIVE
  Inflammatory factors are thought to play a regulatory role in restenosis. Interleukin-10 (IL10) is an important anti-inflammatory cytokine with anti-atherogenic potentials. The aim of this study was to assess the effects of IL10 modulation on cuff-induced neointima formation in hypercholesterolemic APOE*3-Leiden mice.
  
  
  METHODS
  The involvement of IL10 in neointima formation was studied in a hypercholesterolemic mouse model of cuff-induced stenosis of the femoral artery by IL10 knocking-out or overexpression procedures. IL10(+/-) mice were crossbred with APOE*3-Leiden mice to generate hypercholesterolemic APOE*3-LeidenIL10(-/-) mice. To achieve IL10 overexpression in APOE*3-Leiden mice, a single intramuscular injection of a murine IL10 overexpression plasmid was performed followed by electroporation.
  
  
  RESULTS
  Knocking-out IL10, in hypercholesterolemic APOE*3-Leiden mice, resulted in a significant 1.9-fold increase of neointima surface as compared to APOE*3-LeidenIL10(+/+) littermates (p=0.02). Conversely, a marked 45% inhibition on cuff-induced neointima formation was obtained after IL10 overexpression (p=0.02). Electrodelivery of IL10 vector leads to detectable IL10 serum levels, with a sustained expression over the experimental period of 3 weeks. IL10 overexpression reduced plasma cholesterol levels in APOE*3-Leiden mice, whereas IL10 deficiency in these mice did not lead to altered cholesterol levels as compared to the IL10(+/+) group. Finally, IL10 overexpression stimulated endogenous IL10 mRNA expression in the spleen and reduced the transcriptional responses of several pro-inflammatory cytokines.
  
  
  CONCLUSIONS
  Here, we clearly demonstrate the role of IL10 in the development of neointima formation in hypercholesterolemic mice and the potential therapeutic effect of non-viral electrodelivery of IL10 cDNA to inhibit post-angioplasty restenosis.
authors.affiliation: Gaubius Laboratory, TNO-Quality of Life, Leiden, The Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eefting
authors.forename: Abbey
authors.initials: A
authors.lastname: Schepers
authors.forename: Margreet R
authors.initials: MR
authors.lastname: De Vries
authors.forename: Nuno M M
authors.initials: NM
authors.lastname: Pires
authors.forename: Jos M
authors.initials: JM
authors.lastname: Grimbergen
authors.forename: Tonny
authors.initials: T
authors.lastname: Lagerweij
authors.forename: Lex M
authors.initials: LM
authors.lastname: Nagelkerken
authors.forename: Pascalle S
authors.initials: PS
authors.lastname: Monraats
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: J Hajo
authors.initials: JH
authors.lastname: van Bockel
authors.forename: Paul H A
authors.initials: PH
authors.lastname: Quax
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D017539:Tunica Intima / Q000276:immunology*; D014652:Vascular Diseases / Q000235:genetics / Q000276:immunology*
chemical_list: D016753:Interleukin-10