The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE3-Leiden mice

• Published in: Atherosclerosis 2007-08, Vol.193 (2), p.335-342
• Main Authors: Eefting, Daniel, Schepers, Abbey, De Vries, Margreet R, Pires, Nuno M.M, Grimbergen, Jos M, Lagerweij, Tonny, Nagelkerken, Lex M, Monraats, Pascalle S, Jukema, J. Wouter, van Bockel, J. Hajo, Quax, Paul H.A
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular; Cardiovascular system; Cytokines; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Electroporation; Gene therapy; Hypercholesterolemia - genetics; Hypercholesterolemia - immunology; In vivo delivery; Inflammation; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; Medical sciences; Mice; Mice, Knockout; Pharmacology. Drug treatments; Restenosis; Tunica Intima - immunology; Vascular Diseases - genetics; Vascular Diseases - immunology; Vasodilator agents. Cerebral vasodilators
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2006.09.032

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.