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 (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 x 109 plaque-forming units (pfu's) of IL-10 (AdV.IL-10) or control adenovirus (AdV.empty). Administration of AdV.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 1.5x1010 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 AdV.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.
Von Der Thüsen
J H
JH
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, 2300 RA Leiden, The Netherlands.
Kuiper
J
J
Fekkes
M L
ML
De Vos
P
P
Van Berkel
T J
TJ
Biessen
E A
EA
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D002340:Carotid Artery Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy; D002784:Cholesterol / Q000097:blood; D003250:Constriction; D005260:Female; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics* / Q000627:therapeutic use; D008264:Macrophages / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics; D053701:Receptors, Interleukin-10; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D002784:Cholesterol