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Attenuation of atherogenesis by systemic and local adenovirus‐mediated gene transfer of interleukin‐10 in LDLr ‐/‐ Mice
Author(s) -
Thüsen Jan H.,
Kuiper Johan,
Fekkes Madelon L.,
Vos Paula,
Berkel Theo J. C.,
Biessen Erik A. L.
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0483fje
Subject(s) - systemic administration , transfection , systemic inflammation , genetic enhancement , medicine , interleukin 6 , titer , endocrinology , receptor , interleukin , lesion , inflammation , chemistry , pathology , immunology , biology , gene , cytokine , virus , in vivo , biochemistry , microbiology and biotechnology
In view of its multifaceted anti‐inflammatory properties, interleukin‐10 (IL‐10) has been deemed to be potentially anti‐atherogenic. We have evaluated the capacity of adenoviral gene transfer of IL‐10 for the modulation of de novo atherosclerotic lesion formation by systemic and by local overexpression. Atherogenesis was initiated in the carotid arteries of low‐density lipoprotein receptor deficient mice by perivascular placement of silastic collars. One week after collar placement, mice were injected intravenously with 1 × 10 9 plaque‐forming units (pfu's) of IL‐10 (Ad.IL‐10) or control adenovirus (Ad.empty). Administration of Ad.IL‐10 resulted in extended systemic expression of IL‐10 (peak serum level 3.0 ± 1.1 ng/ml) and a reduction in atherosclerotic lumen stenosis by 62.2% ( P < 0.02). This finding was accompanied by monocyte deactivation and lowering of serum cholesterol levels (maximum decrease 44%). In a second experiment, collared arteries were transfected locally by transluminal instillation of adenovirus (titer 1.5×10 10 pfu/ml). Systemic parameters remained unchanged following local transfection, but the degree of stenosis was, nonetheless, decreased by 44.9% ( P < 0.05). We conclude that a marked inhibition of atherogenesis can be achieved by systemic overexpression of Ad.IL‐10, owing to its metabolic and immunomodulatory effects. Local IL‐10 transfer is virtually equipotent, however, and it may represent a valuable addition to the armory of anti‐atherosclerotic therapies.