The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice.
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.
Eefting
Daniel
D
Gaubius Laboratory, TNO-Quality of Life, Leiden, The Netherlands.
Schepers
Abbey
A
De Vries
Margreet R
MR
Pires
Nuno M M
NM
Grimbergen
Jos M
JM
Lagerweij
Tonny
T
Nagelkerken
Lex M
LM
Monraats
Pascalle S
PS
Jukema
J Wouter
JW
van Bockel
J Hajo
JH
Quax
Paul H A
PH
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*
D016753:Interleukin-10