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The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice

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Author: Eefting, D. · Schepers, A. · Vries, M.R. de · Pires, N.M.M. · Grimbergen, J.M. · Lagerweij, T. · Nagelkerken, L.M. · Monraats, P.S. · Jukema, J.W. · Bockel, J.H. van · Quax, P.H.A.
Type:article
Date:2007
Institution: TNO Kwaliteit van Leven
Source:Atherosclerosis, 2, 193, 335-342
Identifier: 240108
doi: doi:10.1016/j.atherosclerosis.2006.09.032
Keywords: Biology · Biomedical Research · Animal models · Cytokines · Electroporation · Gene therapy · In vivo delivery · Inflammation · Restenosis · cytokine · interleukin 10 · animal experiment · animal model · article · cholesterol blood level · controlled study · electroporation · experimental model · gene overexpression · gene transfer · hypercholesterolemia · immunohistochemistry · inflammation · intima · male · morphometrics · mouse · nonhuman · priority journal · restenosis · reverse transcription polymerase chain reaction · RNA isolation · Animals · Disease Models, Animal · Hypercholesterolemia · Interleukin-10 · Mice · Mice, Knockout · Tunica Intima · Vascular Diseases

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. Conclusion: 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. © 2006 Elsevier Ireland Ltd. All rights reserved.