Attenuation of atherogenesis by systemic and local adenovirus-mediated gene transfer of interleukin-10 in LDLr - /- Mice

In view of its multifaceted anti-inflammatory properties, interleukin-10 (I L-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 overexpress ion. Atherogenesis was initiated in the carotid arteries of low-density lip oprotein receptor deficient mice by perivascular placement of silastic coll ars. One week after collar placement, mice were injected intravenously with 1 x 10(9) plaque-forming units (pfu's) of IL-10 (Ad.IL-10) or control aden ovirus (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 i n atherosclerotic lumen stenosis by 62.2% (P<0.02). This finding was accomp anied by monocyte deactivation and lowering of serum cholesterol levels (ma ximum decrease 44%). In a second experiment, collared arteries were transfe cted locally by transluminal instillation of adenovirus (titer 1.5x10(10) p fu/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 s ystemic overexpression of Ad.IL-10, owing to its metabolic and immunomodula tory effects. Local IL-10 transfer is virtually equipotent, however, and it may represent a valuable addition to the armory of antiatherosclerotic the rapies.