(Circulation. 1999;100:1816-1822.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of Apolipoprotein A-I in Mice
From the Department of Medicine, University of Pennsylvania School of Medicine (R.K.T., K.T., D.J.R.), and the Wistar Institute (S.H.C., E.P.), Philadelphia, Pa, and the University of Delaware, Newark (D.U.).
Correspondence to Daniel J. Rader, MD, University of Pennsylvania Medical Center, 409 Stellar Chance Laboratories, 422 Curie Blvd, Philadelphia, PA 19104. E-mail rader{at}mail.med.upenn.edu
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.
Methods and 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.
Key Words: atherosclerosis • liver • genes • apolipoproteins
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