Inhibition of atherogenesis in LDLR knockout mice by systemic delivery of adeno-associated virus type 2-hIL-10.
Atherosclerosis is an inflammatory disease of the arteries. Interleukin-10 (IL-10) is known to be an anti-inflammatory cytokine which might be useful for counteracting the development of atherosclerosis. As long-term systemic cytokine delivery is prohibitively expensive, gene therapy might be a suitable approach. To test this idea, low-density lipoprotein receptor (LDLR) knockout mice were injected with recombinant adeno-associated virus type 2 (AAV)/interleukin-10 virus or AAV/granulocyte macrophage-colony stimulating factor (GM-CSF) virus and then put on a high-cholesterol diet. Upon harvesting the animals at 18 weeks, elevated blood lipids could be documented and AAV/IL-10 and AAV/GM-CSF DNA and mRNA could be found in various mouse organs. The mice receiving the AAV/IL-10 virus had significantly lower levels of atherogenesis (Sudan IV-staining and histology) than the untreated or the AAV/GM-CSF-treated animals, dropping from 53% to 17% (p < 0.05). The aortas of the AAV/IL-10-treated animals displayed higher IL-10 expression and lower CD68 and nitrotyrosine expression. These data are similar to those of Yoshioka et al. [Yoshioka, T, Okada, T, Maeda, Y, et al. Adeno-associatedvirus vector-mediated interleukin-10 gene transfer inhibits atherosclerosis in apolipoprotein E-deficient mice. Gene Ther 2004;11:1772-9] in which AAV/IL-10 was delivered into the tibial muscle of ApoE-deficient mice, instead of tail vein injection used here. These data indicate that systemic AAV/IL-10 gene delivery, with resulting inhibition of inflammation and oxidative stress, was able to limit atherogenesis, and suggest that this approach is worthy of further study.
Liu
Yong
Y
Division of Cardiovascular Medicine, Gene Therapy Program, Department of Internal Medicine, Slot 532, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, AR 72205, USA.
Li
Dayuan
D
Chen
Jiawei
J
Xie
Jin
J
Bandyopadhyay
Sarmistha
S
Zhang
Dazhi
D
Nemarkommula
Aravind R
AR
Liu
Hongmei
H
Mehta
Jawahar L
JL
Hermonat
Paul L
PL
D000818:Animals; D001011:Aorta / Q000737:chemistry; D050197:Atherosclerosis / Q000628:therapy*; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004247:DNA / Q000032:analysis; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000235:genetics
D002791:Cholesterol, Dietary; D012333:RNA, Messenger; D011973:Receptors, LDL; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA