Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice

• Published in: Circulation (New York, N.Y.) Vol. 100; no. 17; pp. 1816 - 1822
• Main Authors: TANGIRALA, R. K, TSUKAMOTO, K, CHUN, S. H, USHER, D, PURE, E, RADER, D. J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 26.10.1999; American Heart Association, Inc
• Subjects: Animals; Aorta - pathology; Apolipoprotein A-I - biosynthesis; Apolipoprotein A-I - genetics; Arteriosclerosis - pathology; Arteriosclerosis - therapy; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Disease Models, Animal; Female; Gene Transfer Techniques; Genetic Therapy; Humans; Lipids - blood; Liver - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Immunohistochemistry; Rodentia; Apolipoprotein AI; Cardiovascular disease; Genetic transfer; Vascular disease; Pathology; Vertebrata; Mammalia; Mouse; Animal; Atherosclerosis; Gene therapy
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.100.17.1816

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. 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. 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.