Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice.
BACKGROUND
The ability of apolipoprotein (apo)A-I to induce regression of preexisting atherosclerotic lesions has not been determined, and a mouse model of atherosclerosis regression has not yet been reported.


RESULTS
LDL receptor-deficient mice were fed a western-type diet for 5 weeks to induce atherosclerotic lesions. A second-generation recombinant adenovirus encoding human apoA-I or a control adenovirus were injected intravenously in order to express apoA-I in the liver. Three days after injection, total apoA-I levels in mice injected with the apoA-I-expressing adenovirus were 216+/-16.0 mg/dL, compared with 68.0+/-3.0 mg/dL in control virus-injected mice (P<0.001). HDL cholesterol levels in mice injected with the AdhapoA-I vector 7 days after injection were 189+/-21.0 mg/dL, compared with 123+/-8.0 mg/dL in control virus-injected mice (P<0.02). Total and non-HDL cholesterol levels did not differ between the 2 groups. Atherosclerotic lesion area was quantified by en face analysis of the aorta and cross-sectional analysis of the aortic root. Compared with baseline mice, atherosclerosis progressed in mice injected with the control adenovirus. In contrast, in mice expressing apoA-I compared with baseline mice, total en face aortic lesion area was reduced by 70% and aortic root lesion was reduced by 46%. Expression of apoA-I was associated with a significant reduction in the fraction of lesions occupied by macrophages and macrophage-derived foam cells.


CONCLUSIONS
Liver-directed gene transfer of human apoA-I resulted in significant regression of preexisting atherosclerotic lesions in LDL receptor-deficient mice as assessed by 2 independent methods.
Tangirala
R K
RK
Department of Medicine, University of Pennsylvania School of Medicine Philadelphia, PA, USA.
Tsukamoto
K
K
Chun
S H
SH
Usher
D
D
Puré
E
E
Rader
D J
DJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000235:genetics*; D001161:Arteriosclerosis / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
D016632:Apolipoprotein A-I; D008055:Lipids