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

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• 作者：Daniel Eefting ; Abbey Schepers ; Margreet R. De Vries ; Nuno M.M. Pires ; Jos M. Grimbergen ; Tonny Lagerweij ; Lex M. Nagelkerken ; Pascalle S. Monraats ; J. Wouter Jukema ; J. Hajo van Bockel ; Paul H.A. Qu
• 关键词：Restenosis ; Cytokines ; Electroporation ; Gene therapy ; In vivo delivery ; Inflammation ; Animal models
• 刊名：Atherosclerosis
• 出版年：2007
• 期刊代码：28_00219150
• 类别：med
• 出版时间：August 2007
• 卷：193
• 期：2
• 页码：335-342
• 文件大小：623 K

摘要

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.