title: Acute regression of advanced and retardation of early aortic atheroma in immunocompetent apolipoprotein-E (apoE) deficient mice by administration of a second generation [E1(-), E3(-), polymerase(-)] adenovirus vector expressing human apoE.
abstract: Apolipoprotein E (apoE) is a 34 kDa glycoprotein with multiple actions that help protect against the development of atherosclerosis. Here, we have assessed the atheroprotective potential of an [E1(-), E3(-), polymerase(-)] adenovirus vector expressing human apoE, comparing intramuscular and intravenous (liver-directed) injections in hypercholesterolaemic apoE-deficient mice (apoE(-/-)). Intramuscular injections resulted in low expression of apoE and afforded no protection against atherogenesis. In contrast, 3 and 7 days after intravenous injections into young (6-8-week-old) apoE(-/-) mice, plasma levels of apoE were elevated and were accompanied by reductions in plasma cholesterol and normalization of lipoprotein profiles. Thereafter, plasma apoE was still detectable up to day 70, but gradually declined, although no humoral immune response was evoked, and there was a return to dyslipoproteinaemia. High levels of the vector genome were still present in livers of treated animals at 70 days, implying that decrease in apoE expression was due to cellular shutdown of the cytomegalovirus promoter. Importantly, liver-directed apoE gene transfer to these young mice retarded progression of atherosclerosis by 38% (treated, 8.21 +/- 1.05%; untreated, 13.26 +/- 0.98%, P < 0.05), during the 70 day study period. Moreover, when 10-month-old apoE(-/-) mice with advanced atherosclerosis were treated with the adenovirus vector, there was clear regression of aortic lesion area by 1 month [24.3 +/- 1.7% compared to 40.7 +/- 2.6% in baseline controls (P < 0.002)]. We conclude that the stability of the adenovirus vector genome in the livers of intravenously treated animals provides an ideal platform to evaluate liver-specific promoters for sustained transgene expression and control of atherosclerotic lesion pathology.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK.
authors.forename: Julian D
authors.initials: JD
authors.lastname: Harris
authors.forename: Ian R
authors.initials: IR
authors.lastname: Graham
authors.forename: Silke
authors.initials: S
authors.lastname: Schepelmann
authors.forename: Anita K
authors.initials: AK
authors.lastname: Stannard
authors.forename: Michael L
authors.initials: ML
authors.lastname: Roberts
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Hodges
authors.forename: Vanessa
authors.initials: V
authors.lastname: Hill
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
authors.forename: David G
authors.initials: DG
authors.lastname: Hassall
authors.forename: James S
authors.initials: JS
authors.lastname: Owen
authors.forename: George
authors.initials: G
authors.lastname: Dickson
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D001161:Arteriosclerosis / Q000235:genetics / Q000517:prevention & control*; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D017931:DNA Primers / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001057:Apolipoproteins E; D017931:DNA Primers; D008055:Lipids; D008074:Lipoproteins; D002784:Cholesterol